Benzoimidazoles as prolyl hydroxylase inhibitors

ABSTRACT

and enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof. Compounds of the present invention are useful in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions modulated by prolyl hydroxylase activity.

FIELD OF THE INVENTION

The present invention relates to certain benzoimidazole compounds,pharmaceutical compositions containing them, and methods of using themfor the treatment of disease states, disorders, and conditions mediatedby prolyl hydroxylase activity.

BACKGROUND OF THE INVENTION

Cells respond to hypoxia by activating the transcription of genesinvolved in cell survival, oxygen delivery and utilization,angiogenesis, cellular metabolism, regulation of blood pressure,hematopoiesis, and tissue preservation. Hypoxia-inducible factors (HIFs)are key transcriptional regulators of these genes (Semenza et al., 1992,Mol Cell Biol., 12(12):5447-54; Wang et al., 1993, J Biol Chem.,268(29):21513-18; Wang et al., 1993, Proc Natl Acad Sci., 90:4304-08;Wang et al., 1995, J Biol Chem., 270(3):1230-37). Three forms of HIF-αhave been described: HIF-1α, HIF-2α and HIF-3α (Scheuermann et al.,2007, Methods Enzymol., 435:3-24). Pairing of a HIFα sub-unit withHIF-1β forms a functional heterodimeric protein that subsequentlyrecruits other transcriptional factors such as p300 and CBP (Semenza,2001, Trends Mol Med., 7(8):345-50).

A family of highly conserved oxygen, iron, and 2-oxoglutarate-dependentprolyl hydroxylase (PHD) enzymes mediate the cells response to hypoxiavia post-translational modification of HIF (Ivan et al., 2001, Science,292:464-68; Jaakkola et al., 2001, Science, 292:468-72). Under normoxicconditions, PHD catalyzes the hydroxylation of two conserved prolineresidues within HIF. Von Hippel Lindau (VHL) protein binds selectivelyto hydroxylated HIF. The binding of VHL renders HIF a target forpolyubiquitination by the E3 ubiquitin ligase complex and its subsequentdegradation by the 26S proteasome (Ke et al., 2006, Mol Pharmacol.70(5):1469-80; Semenza, Sci STKE., 2007, 407(cm8):1-3). As the affinityof PHD for oxygen is within the physiological range of oxygen and oxygenis a necessary co-factor for the reaction, PHD is inactivated whenoxygen tension is reduced. In this way, HIF is rapidly degraded undernormoxic conditions but accumulates in cells under hypoxic conditions orwhen PHD is inhibited.

Four isotypes of PHD have been described: PHD1, PHD2, PHD3, and PHD4(Epstein et al., 2001, Cell, 107:43-54; Kaelin, 2005, Annu Rev Biochem.,74:115-28; Schmid et al., 2004, J Cell Mol Med., 8:423-31). Thedifferent isotypes are ubiquitously expressed but are differentiallyregulated and have distinct physiological roles in the cellular responseto hypoxia. There is evidence that the various isotypes have differentselectivity for the three different HIFα sub-types (Epstein et al.,supra). In terms of cellular localization, PHD1 is primarily nuclear,PHD2 is primarily cytoplasmic, and PHD3 appears to be both cytoplasmicand nuclear (Metzen E, et al. 2003, J Cell Sci., 116(7):1319-26). PHD2appears to be the predominant HIFα prolyl hydroxylase under normoxicconditions (Ivan et al., 2002. Proc Natl Acad Sci. USA, 99(21):13459-64;Berra et al., 2003, EMBO J., 22:4082-90). The three isotypes have a highdegree of amino-acid homology and the active site of the enzyme ishighly conserved.

The HIF target gene products are involved in a number of physiologicaland pathophysiological processes including but not limited to:erythropoiesis, angiogenesis, regulation of energy metabolism, vasomotorfunction, and cell apoptosis/proliferation. The first gene described asa HIF target was that encoding erythropoietin (EPO) (Wang et al., 1993,supra). It was recognized that a reduction in the oxygen carryingcapacity of the blood is sensed in the kidney and that the kidney andliver respond by releasing more EPO, the hormone that stimulates redblood cell proliferation and maturation. EPO has a number of otherimportant effects on non-hematopoietic cell types and has emerged as akey tissue-protective cytokine (Arcasoy, 2008, Br J Haematol.,141:14-31). Thus EPO is now implicated in wound healing and angiogenesisas well as the response of tissues to ischemic insult. Most of theenzymes involved in anaerobic glycolysis are encoded by HIF target genesand as a result glycolysis is increased in hypoxic tissues (Shaw, 2006,Curr Opin Cell Biol., 18(6):598-608). The known HIF target gene productsin this pathway include but are not limited to: glucose transporterssuch as GLUT-1 (Ebert et al., 1995, J Biol Chem., 270(49):29083-89),enzymes involved in the break down of glucose to pyruvate such ashexokinase and phosphoglycerate kinase 1 (Firth et al., 1994, Proc NatlAcad Sci. USA, 91:6496-6500) as well as lactate dehydrogenase (Firth etal., supra). HIF target gene products are also involved in theregulation of cellular metabolism. For example, pyruvate dehydrogenasekinase-1 is a target HIF gene product and regulates the entry ofpyruvate into the Kreb's cycle by reducing the activity of pyruvatedehydrogenase by phosphorylation (Kim et al., 2006, Cell Metab.,3:177-85; Papandreou et al., 2006, Cell Metab., 3:187-197). HIF targetgene products are also involved in angiogenesis. For example, vascularendothelial growth factor (VEGF) (Liu et al., 1995, Circ Res.,77(3):638-43) is a known regulator of angiogenesis and vasculogenesis.HIF target gene products also function in the regulation of vasculartone and include heme oxygenase-1 (Lee et al., 1997, J Biol Chem.,272(9):5375-81). A number of HIF regulated gene products such asplatelet-derived growth factor (PDGF) (Yoshida et al., 2006, JNeurooncol., 76(1):13-21), vascular endothelial growth factor (Breen,2007, J Cell Biochem., 102(6):1358-67) and EPO (Arcasoy, supra) alsofunction in the coordinated response to wound healing.

Targeted disruption of the prolyl hydroxylase (PHD) enzyme activity bysmall molecules has potential utility in the treatment of disorders ofoxygen sensing and distribution. Examples include but are not limitedto: anemia; sickle cell anemia; peripheral vascular disease; coronaryartery disease; heart failure; protection of tissue from ischemia inconditions such as myocardial ischemia, myocardial infarction andstroke; preservation of organs for transplant; treatment of tissueischemia by regulating and/or restoring blood flow, oxygen deliveryand/or energy utilization; acceleration of wound healing particularly indiabetic and aged patients; treatment of burns; treatment of infection;bone healing, and bone growth. In addition, targeted disruption of PHDis expected to have utility in treating metabolic disorders such asdiabetes, obesity, ulcerative colitis, inflammatory bowel disease andrelated disorders such as Crohn's disease. (Recent Patents onInflammation & Allergy Drug Discovery, 2009, 3, 1-16).

HIF has been shown to be the primary transcriptional factor that leadsto increased erythropoietin production under conditions of hypoxia (Wanget al., 1993, supra). While treatment with recombinant humanerythropoietin has been demonstrated to be an effective method oftreating anemia, small molecule mediated PHD inhibition can be expectedto offer advantages over treatment with erythropoietin. Specifically,the function of other HIF gene products are necessary for hematopoesisand regulation of these factors increases the efficiency ofhematopoesis. Examples of HIF target gene products that are critical forhematopoesis include: transferrin (Rolfs et al., 1997, J Biol Chem.,272(32):20055-62), transferrin receptor (Lok et al., 1999, J Biol Chem.,274(34):24147-52; Tacchini et al., 1999, J Biol Chem., 274(34):24142-46)and ceruloplasmin (Mukhopadhyay et al., 2000, J Biol Chem.,275(28):21048-54). Hepcidin expression is also suppressed by HIF(Peyssonnaux et al., 2007, J Clin Invest., 117(7):1926-32) and smallmolecule inhibitors of PHD have been shown to reduce hepcidin production(Braliou et al., 2008, J Hepatol., 48:801-10). Hepcidin is a negativeregulator of the availability of the iron that is necessary forhematopoesis, so a reduction in hepcidin production is expected to bebeneficial to the treatment of anemia. PHD inhibition may also be usefulwhen used in conjunction with other treatments for anemia including ironsupplementation and/or exogenous erythropoietin. Studies of mutations inthe PHD2 gene occurring naturally in the human population providefurther evidence for the use of PHD inhibitors to treat anemia. Tworecent reports have shown that patients with dysfunctional mutations inthe PHD2 gene display increased erythrocytosis and elevated bloodhemoglobin (Percy et al., 2007, PNAS, 103(3):654-59; Al-Sheikh et al.,2008, Blood Cells Mol Dis., 40:160-65). In addition, a small moleculePHD inhibitor has been evaluated in healthy volunteers and patients withchronic kidney disease (U.S. pat. appl. US2006/0276477, Dec. 7, 2006).Plasma erythropoietin was increased in a dose-dependent fashion andblood hemoglobin concentrations were increased in the chronic kidneydisease patients.

Metabolic adaptation and preservation of tissues are jeopardized byischemia. PHD inhibitors increase the expression of genes that lead tochanges in metabolism that are beneficial under ischemic conditions(Semenza, 2007, Biochem J., 405:1-9). Many of the genes encoding enzymesinvolved in anaerobic glycolysis are regulated by HIF and glycolysis isincreased by inhibiting PHD (Shaw, supra). Known HIF target genes inthis pathway include but are not limited to: GLUT-1 (Ebert et al.,supra), hexokinase, phosphoglycerate kinase 1, lactate dehydrogenase(Firth et al., supra), pyruvate dehydrogenase kinase-1 (Kim et al.,supra; Papandreou et al., supra). Pyruvate dehydrogenase kinase-1suppresses the entry of pyruvate into the Kreb's cycle. HIF mediates aswitch in the expression of the cytochromes involved in electrontransport in the mitochondria (Fukuda et al., 2007, Cell,129(1):111-22). This change in the cytochrome composition optimizes theefficiency in ATP production under hypoxic conditions and reduces theproduction of injurious oxidative phosphorylation by-products such ashydrogen peroxide and superoxide. With prolonged exposure to hypoxia,HIF drives autophagy of the mitochondria resulting a reduction in theirnumber (Zhang H et al., 2008, J Biol Chem. 283: 10892-10903). Thisadaptation to chronic hypoxia reduces the production of hydrogenperoxide and superoxide while the cell relies on glycolysis to produceenergy. A further adaptive response produced by HIF elevation isup-regulation of cell survival factors. These factors include:Insulin-like growth factor (IGF) 2, IGF-binding protein 2 and 3 (Feldseret al., 1999, Cancer Res. 59:3915-18). Overall accumulation of HIF underhypoxic conditions governs an adaptive up-regulation of glycolysis, areduction in oxidative phosphorylation resulting in a reduction in theproduction of hydrogen peroxide and superoxide, optimization ofoxidative phosphorylation protecting cells against ischemic damage.Thus, PHD inhibitors are expected to be useful in organ and tissuetransplant preservation (Bernhardt et al., 2007, Methods Enzymol.,435:221-45). While benefit may be achieved by administering PHDinhibitors before harvesting organs for transplant, administration of aninhibitor to the organ/tissue after harvest, either in storage (e.g.,cardioplegia solution) or post-transplant, may also be of therapeuticbenefit.

PHD inhibitors are expected to be effective in preserving tissue fromregional ischemia and/or hypoxia. This includes ischemia/hypoxiaassociated with inter alia: angina, myocardial ischemia, stroke,ischemia of skeletal muscle. There are a number of lines of experimentalevidence that support the concept that PHD inhibition and subsequentelevation of HIF as a useful method for preserving ischemic tissue.Recently, ischemic pre-conditioning has been demonstrated to be aHIF-dependent phenomenon (Cai et al., 2008, Cardiovasc Res.,77(3):463-70). Ischemic pre-conditioning is a well known phenomenonwhereby short periods of hypoxia and/or ischemia protect tissue fromsubsequent longer periods of ischemia (Murry et al., 1986, Circulation,1986 74(5):1124-36; Das et al., 2008, IUBMB Life, 60(4):199-203).Ischemic pre-conditioning is known to occur in humans as well asexperimental animals (Darling et al., 2007, Basic Res Cardiol.,102(3):274-8; Kojima I et al., 2007, J Am Soc Nephrol., 18:1218-26).While the concept of pre-conditioning is best known for its protectiveeffects in the heart, it also applies to other tissues including but notlimited to: liver, skeletal muscle, liver, lung, kidney, intestine andbrain (Pasupathy et al., 2005, Eur J Vasc Endovasc Surg., 29:106-15;Mallick et al., 2004, Dig Dis Sci., 49(9):1359-77). Experimentalevidence for the tissue protective effects of PHD inhibition andelevation of HIF have been obtained in a number of animal modelsincluding: germ-line knock out of PHD1 which conferred protection of theskeletal muscle from ischemic insult (Aragones et al., 2008, Nat Genet.,40(2):170-80), silencing of PHD2 through the use of siRNA whichprotected the heart from ischemic insult (Natarajan et al., 2006, CircRes., 98(1):133-40), inhibition of PHD by administering carbon monoxidewhich protected the myocardium from ischemic injury (Chin et al., 2007,Proc Natl Acad Sci. U.S.A., 104(12):5109-14), hypoxia in the brain whichincreased the tolerance to ischemia (Bernaudin et al., 2002, J CerebBlood Flow Metab., 22(4):393-403). In addition, small moleculeinhibitors of PHD protect the brain in experimental stroke models(Siddiq et al., 2005, J Biol Chem., 280(50):41732-43). Moreover, HIFup-regulation has also been shown to protect the heart of diabetic mice,where outcomes are generally worse (Natarajan et al., 2008, J CardiovascPharmacol., 51(2):178-187). The tissue protective effects may also beobserved in Buerger's disease, Raynaud's disease, and acrocyanosis.

The reduced reliance on aerobic metabolism via the Kreb's cycle in themitochondria and an increased reliance on anaerobic glycolysis producedby PHD inhibition may have beneficial effects in normoxic tissues. It isimportant to note that PHD inhibition has also been shown to elevate HIFunder normoxic conditions. Thus, PHD inhibition produces a pseudohypoxiaassociated with the hypoxic response being initiated through HIF butwith tissue oxygenation remaining normal. The alteration of metabolismproduced by PHD inhibition can also be expected to provide a treatmentparadigm for diabetes, obesity and related disorders, includingco-morbidities.

Globally, the collection of gene expression changes produced by PHDinhibition reduce the amount of energy generated per unit of glucose andwill stimulate the body to burn more fat to maintain energy balance. Themechanisms for the increase in glycolysis are discussed above. Otherobservations link the hypoxic response to effects that are expected tobe beneficial for the treatment of diabetes and obesity. Thus, highaltitude training is well known to reduce body fat (Armellini et al.,1997, Horm Metab Res., 29(9):458-61). Hypoxia and hypoxia mimetics suchas desferrioxamine have been shown to prevent adipocyte differentiation(Lin et al., 2006, J Biol Chem., 281(41):30678-83; CarriBre et al.,2004, J Biol Chem., 279(39):40462-69). The effect is reversible uponreturning to normoxic conditions. Inhibition of PHD activity during theinitial stages of adipogenesis inhibits the formation of new adipocytes(Floyd et al., 2007, J Cell Biochem., 101:1545-57). Hypoxia, cobaltchloride and desferrioxamine elevated HIF and inhibited PPAR gamma 2nuclear hormone receptor transcription (Yun et al., 2002, Dev Cell.,2:331-41). As PPAR gamma 2 is an important signal for adipocytedifferentiation, PHD inhibition can be expected to inhibit adipocytedifferentiation. These effects were shown to be mediated by theHIF-regulated gene DEC1/Stra13 (Yun et al., supra).

Small molecular inhibitors of PHD have been demonstrated to havebeneficial effects in animal models of diabetes and obesity (Intl. Pat.Appl. Publ. WO2004/052284, Jun. 24, 2004; WO2004/052285, Jun. 24, 2004).Among the effects demonstrated for PHD inhibitors in mouse diet-inducedobesity, db/db mouse and Zucker fa/fa rat models were lowering of: bloodglucose concentration, fat mass in both abdominal and visceral fat pads,hemoglobin A1c, plasma triglycerides, body weight as well as changes inestablished disease bio-markers such as increases in the levels ofadrenomedullin and leptin. Leptin is a known HIF target gene product(Grosfeld et al., 2002, J Biol Chem., 277(45):42953-57). Gene productsinvolved in the metabolism in fat cells were demonstrated to beregulated by PHD inhibition in a HIF-dependent fashion (Intl. Pat. Appl.Publ. WO2004/052285, supra). These include apolipoprotein A-IV, acyl CoAthioesterase, carnitine acetyl transferase, and insulin-like growthfactor binding protein (IGFBP)-1.

PHD inhibitors are expected to be therapeutically useful as stimulantsof vasculogenesis, angiogenesis, and arteriogenesis. These processesestablish or restore blood flow and oxygenation to the tissues underischemia and/or hypoxia conditions (Semenza et al., 2007, J CellBiochem., 102:840-47; Semenza, 2007, Exp Physiol., 92(6):988-91). It hasbeen shown that physical exercise increases HIF-1 and vascularendothelial growth factor in experimental animal models and in humans(Gustafsson et al. 2001, Front Biosci., 6: D75-89) and consequently thenumber of blood vessels in skeletal muscle. VEGF is a well-known HIFtarget gene product that is a key driver of angiogenesis (Liu et al.,supra). While administration of various forms of VEGF receptoractivators are potent stimuli for angiogenesis, the blood vesselresulting from this potential form of therapy are leaky. This isconsidered to limit the potentially utility of VEGF for the treatment ofdisorders of oxygen delivery. The increased expression of a singleangiogenic factor may not be sufficient for functional vascularization(Semenza, 2007, supra). PHD inhibition offers a potential advantage overother such angiogenic therapies in that it stimulates a controlledexpression of multiple angiogenic growth factors in a HIF-dependentfashion including but not limited to: placental growth factor (PLGF),angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), platelet-derivedgrowth factor beta (PDGFB) (Carmeliet, 2004, J Intern Med., 255:538-61;Kelly et al., 2003, Circ Res., 93:1074-81) and stromal cell derivedfactor 1 (SDF-1) (Ceradini et al., 2004, Nat Med., 10(8):858-64).Expression of angiopoietin-1 during angiogenesis producesleakage-resistant blood vessels, in contrast to the vessels produced byadministration of VEGF alone (Thurston et al., 1999, Science,286:2511-14; Thurston et al., 2000, Nat Med., 6(4):460-3; Elson et al.,2001, Genes Dev., 15(19):2520-32). Stromal cell derived factor 1 (SDF-1)has been shown to be critical to the process of recruiting endothelialprogenitor cells to the sites of tissue injury. SDF-1 expressionincreased the adhesion, migration and homing of circulatingCXCR4-positive progenitor cells to ischemic tissue. Furthermoreinhibition of SDF-1 in ischemic tissue or blockade of CXCR4 oncirculating cells prevents progenitor cell recruitment to sites ofinjury (Ceradini et al., 2004, supra; Ceradini et al., 2005, TrendsCardiovasc Med., 15(2):57-63). Importantly, the recruitment ofendothelial progenitor cells to sites of injury is reduced in aged miceand this is corrected by interventions that increase HIF at the woundsite (Chang et al., 2007, Circulation, 116(24):2818-29). PHD inhibitionoffers the advantage not only of increasing the expression of a numberof angiogenic factions but also a co-ordination in their expressionthroughout the angiogenesis process and recruitment of endothelialprogenitor cells to ischemic tissue.

Evidence for the utility of PHD inhibitors as pro-angiogenic therapiesis provided by the following observations. Adenovirus-mediatedover-expression of HIF has been demonstrated to induce angiogenesis innon-ischemic tissue of an adult animal (Kelly et al., 2003, Circ Res.,93(11):1074-81) providing evidence that therapies that elevate HIF, suchas PHD inhibition, will induce angiogenesis. Placental growth factor(PLGF), also a HIF target gene, has been show to play a critical role inangiogenesis in ischemic tissue (Carmeliet, 2004, J Intern Med.,255(5):538-61; Luttun et al., 2002, Ann N YAcad Sci., 979:80-93). Thepotent pro-angiogenic effects of therapies that elevate HIF have beendemonstrated, via HIF over-expression, in skeletal muscle (Pajusola etal., 2005, FASEB J., 19(10):1365-7; Vincent et al., 2000, Circulation,102:2255-61) and in the myocardium (Shyu et al., 2002, Cardiovasc Res.,54:576-83). The recruitment of endothelial progenitor cells to theischemic myocardium by the HIF target gene SDF-1 has also beendemonstrated (Abbott et al., 2004, Circulation, 110(21):3300-05). Thesefindings support the general concept that PHD inhibitors will beeffective in stimulating angiogenesis in the setting of tissue ischemia,particularly muscle ischemia. It is expected that therapeuticangiogenesis produced by PHD inhibitors will be useful in restoringblood flow to tissues and therefore the treatment of disease includingbut not restricted to angina pectoris, myocardial ischemia andinfarction, peripheral ischemic disease, claudication, gastric andduodenal ulcers, ulcerative colitis, and inflammatory bowel disease.

PHD and HIF play a central role in tissue repair and regenerationincluding healing of wounds and ulcers. Recent studies have demonstratedthat an increased expression of all three PHDs at wound sites in agedmice with a resulting reduction in HIF accumulation (Chang et al.,supra). Thus, elevation of HIF in aged mice by administeringdesferrioxamine increased the degree of wound healing back to levelsobserved in young mice. Similarly, in a diabetic mouse model, HIFelevation was suppressed compared to non-diabetic litter mates (Mace etal., 2007, Wound Repair Regen., 15(5):636-45). Topical administration ofcobalt chloride, a hypoxia mimetic, or over-expression of a murine HIFthat lacks the oxygen-dependent degradation domain and thus provides fora constitutively active form of HIF, resulted in increased HIF at thewound site, increased expression of HIF target genes such as VEGF, Nos2,and Hmox1 and accelerated wound healing. The beneficial effect of PHDinhibition is not restricted to the skin and small molecule inhibitorsof PHD have recently been demonstrated to provide benefit in a mousemodel of colitis (Robinson et al., 2008, Gastroenterology,134(1):145-55).

PHD inhibition resulting in accumulation of HIF is expected to act by atleast four mechanisms to contribute to accelerated and more completehealing of wounds and burns: 1) protection of tissue jeopardized byhypoxia and/or ischemia, 2) stimulation of angiogenesis to establish orrestore appropriate blood flow to the site, 3) recruitment ofendothelial progenitor cells to wound sites, 4) stimulation of therelease of growth factors that specifically stimulate healing andregeneration.

Recombinant human platelet-derived growth factor (PDGF) is marketed asbecaplermin (Regranex™) and has been approved by the Food and DrugAdministration of the United States of America for “Treatment of lowerextremity diabetic neuropathic ulcers that extend into the subcutaneoustissue or beyond, and have adequate blood supply”. Becaplermin has beenshown to be effective in accelerating wound healing in diabetic patients(Steed, 2006, Plast Reconstr Surg., 117(7 Suppl):143S-149S; Nagai etal., 2002, Expert Opin Biol Ther, 2(2):211-8). As PDGF is a HIF genetarget (Schultz et al., 2006, Am J Physiol Heart Circ Physiol.,290(6):H2528-34; Yoshida et al., 2006, J Neurooncol., 76(1):13-21), PHDinhibition is expected to increase the expression of endogenous PDGF andproduce a similar or more beneficial effect to those produced withbecaplermin alone. Studies in animals have shown that topicalapplication of PDGF results in increased wound DNA, protein, andhydroxyproline amounts; formation of thicker granulation and epidermaltissue; and increased cellular repopulation of wound sites. PDGF exertsa local effect on enhancing the formation of new connective tissue. Theeffectiveness of PHD inhibition is expected to be greater than thatproduced by becaplermin due to the additional tissue protective andpro-angiogenic effects mediated by HIF.

The beneficial effects of inhibition of PHD are expected to extend notonly to accelerated wound healing in the skin and colon but also to thehealing of other tissue damage including but not limited togastrointestinal ulcers, skin graft replacements, burns, chronic woundsand frost bite.

Stem cells and progenitor cells are found in hypoxic niches within thebody and hypoxia regulates their differentiation and cell fate (Simon etal., 2008, Nat Rev Mol Cell Biol., 9:285-96). Thus PHD inhibitors may beuseful to maintain stem cells and progenitor cells in a pluripotentstate and to drive differentiation to desired cell types. Stem cells maybe useful in culturing and expanding stem cell populations and may holdcells in a pluripotent state while hormones and other factors areadministered to the cells to influence the differentiation and cellfate.

A further use of PHD inhibitors in the area of stem cell and progenitorcell therapeutics relates to the use of PHD inhibitors to conditionthese cells to withstand the process of implantation into the body andto generate an appropriate response to the body to make the stem celland progenitor cell implantation viable (Hu et al., 2008, J ThoracCardiovasc Surg., 135(4):799-808). More specifically PHD inhibitors mayfacilitate the integration of stem cells and draw in an appropriateblood supply to sustain the stem cells once they are integrated. Thisblood vessel formation will also function to carry hormones and otherfactors released from these cells to the rest of the body.

PHD inhibitors may also be useful in the treatment of infection(Peyssonnaux et al., 2005, J Invest Dermatol., 115(7):1806-15;Peyssonnaux et al., 2008 J Invest Dermatol., 2008 August;128(8):1964-8). HIF elevation has been demonstrated to increase theinnate immune response to infection in phagocytes and in keratinocytes.Phagocytes in which HIF is elevated show increased bacteriacidalactivity, increased nitric oxide production and increased expressed ofthe anti-bacterial peptide cathelicidin. These effects may also beuseful in treating infection from burns.

HIF has also been shown to be involved in bone growth and healing(Pfander D et al., 2003 J Cell Sci., 116(Pt 9):1819-26., Wang et al.,2007 J Clin Invest, 17(6):1616-26.) and may therefore be used to heal orprevent fractures. HIF stimulates of glycolysis to provide energy toallow the synthesis of extracellular matrix of the epiphysealchondrocytes under a hypoxic environment. HIF also plays a role indriving the release of VEGF and angiogenesis in bone healing process.The growth of blood vessels into growing or healing bone can be the ratelimiting step in the process.

Certain small molecules with Prolyl Hydroxylase antagonistic activitieshave been described in the literature. These include, but are notlimited to, certain imidazo[1,2-a]pyridine derivatives (Warshakoon etal., 2006, Bioorg Med Chem Lett., 16(21):5598-601), substituted pyridinederivatives (Warshakoon et al., 2006, Bioorg Med Chem Lett.,16(21):5616-20), certain pyrazolopyridines (Warshakoon et al., 2006,Bioorg Med Chem Lett., 16(21):5687-90), certain bicyclic heteroaromaticN-substituted glycine derivatives (Intl. Pat. Appl. Publ. WO2007/103905,Sep. 13, 2007), quinoline based compounds (Intl. Pat. Appl. Publ.WO2007/070359, Jun. 21, 2007), certain pyrimidinetrione N-substitutedglycine derivatives (Intl. Pat. Appl. Publ. WO2007/150011, Dec. 27,2007), and substituted aryl or heteroaryl amide compounds (U.S. Pat.Appl. Publ. No.: US 2007/0299086, Dec. 27, 2007).

Certain benzoimidazole derivatives have been disclosed in theliterature. For example, LeCount et al., Journal of the ChemicalSociety, Perkin Transactions 1: Organic and Bio-Organic Chemistry(1972-1999) (1974), (2):297-301, Senga et al., Journal of HeterocyclicChemistry (1975), 12(5):899-901, Kandeel et al., Polish Journal ofChemistry (1983), 57(1-3), 327-31, Povstyanoi et al., UkrainskiiKhimicheskii Zhurnal (Russian Edition) (1990), 56(10):1089-92, Singh etal., Indian Journal of Chemistry, Section B: Organic Chemistry IncludingMedicinal Chemistry, (1993) 32B(2):262-5, Lipunova et al., MendeleevCommunications (1996), (1):15-17, Lipunova et al., Russian Journal ofOrganic Chemistry (Translation of Zhurnal Organicheskoi, Khimii) (1997),33(10):1476-86, benzoimidazole-pyrazoles intermediates for NHE-1inhibitors (WO9943663), N-Heteroarylimidazoles as psychopharmaceuticals(DE3824658). Additionally,1-(1H-Benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid (CASNo. 1017666-26-0),1-(1H-benzoimidazol-2-yl)-5-hydroxy-1H-pyrazole-4-carboxylic acid ethylester (CAS No. 1006582-96-2),1-(1H-benzoimidazol-2-yl)-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid(CAS No. 1017666-37-3), and1-(1H-benzoimidazol-2-yl)-5-(2,5-dimethyl-pyrrol-1-yl)-1H-pyrazole-4-carboxylicacid (CAS No. 1017666-50-0) are commercially available.

However, there remains a need for potent prolyl hydroxylase modulatorswith desirable pharmaceutical properties. Notwithstanding the above, thepresent invention is directed to novel benzoimidazole derivatives whichare useful for this purpose.

SUMMARY OF THE INVENTION

The present invention is generally directed to compounds that are PHDinhibitors and are of the formula (I),

wherein:

-   n is 2-4;-   R¹ is independently selected from H, halo, —C₁₋₄alkyl,    —C₃₋₈cycloalkyl, —C₁₋₄perhaloalkyl, trifluoroC₁₋₄alkoxy, —OH, —NO₂,    —CN, CO₂H, —OC₁₋₄alkyl, —SC₁₋₄alkyl, —S(C₁₋₄alkyl)-R^(c),    —S(O)₂(C₁₋₄alkyl)-R^(c), —S(O)—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl, —S—R^(c),    —S(O)—R^(c), —SO₂—R^(c), —SO₂—NH—R^(d), —O—R^(c), —CH₂—O—R^(c),    —C(O)NH—R^(c), —NR^(a)R^(b), benzyloxy optionally substituted with    R^(d), phenyl or monocyclic heteroaryl optionally substituted with    one or more R^(d), —C₃₋₈cycloalkyl optionally containing O, S or N    wherein said —C₃₋₈cycloalkyl is optionally substituted with R^(d),    and two adjacent R¹ groups may be joined to form an optionally    substituted 3-8 member ring optionally containing one or more O, S    or N;-   R^(a) and R^(b) are each independently H, C₁₋₄alkyl, —C(O)C₁₋₄alkyl,    —C(O)—R^(C), —C(O)CH₂—R^(e), C₁₋₄alkyl-R^(e), —SO₂—R^(c),    —SO₂—C₁₋₄alkyl, phenyl optionally substituted with R^(d), benzyl    optionally substituted with R^(d) or monocyclic heteroaryl ring    optionally substituted with R^(d); or R^(a) and R^(b) can be taken    together with the nitrogen to which they are attached to form an    optionally substituted monocyclic heterocycloalkyl ring optionally    containing one or more O, S or N;-   R^(c) is —C₃₋₈cycloalkyl, phenyl optionally substituted with R^(d),    benzyl optionally substituted with R^(d), or a monocyclic heteroaryl    ring optionally substituted with R^(d);-   R^(d) is independently —H, halo, —OH, —C₁₋₄alkyl or    —C₁₋₄perhaloalkyl, trifluoroC₁₋₄alkoxy, —OC₁₋₄alkyl, —O-phenyl, or    —O-benzyl;-   R^(e) is —C₃₋₈heterocycloalkyl optionally containing one or more O,    S or N;-   R² and R³ are both H, —CF₃, or —CH₃; and-   each Z is C or N, provided that no more than two Zs can    simultaneously be N; and    enantiomers, diastereomers, racemates thereof, or pharmaceutically    acceptable salts thereof.

Isomeric forms of the compounds of formula (I), and of theirpharmaceutically acceptable salts, are encompassed within the presentinvention, and reference herein to one of such isomeric forms is meantto refer to at least one of such isomeric forms. One of ordinary skillin the art will recognize that compounds according to this invention mayexist, for example, in a single isomeric form whereas other compoundsmay exist in the form of a regioisomeric mixture.

The invention also relates to pharmaceutically acceptable salts,pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites of compounds of Formula (I). In certain preferredembodiments, the compound of Formula (I) is a compound selected fromthose species described or exemplified in the detailed descriptionbelow.

In a further general aspect, the invention relates to pharmaceuticalcompositions each comprising: (a) an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable prodrug, or pharmaceutically active metabolite thereof; and(b) a pharmaceutically acceptable excipient.

In another general aspect, the invention is directed to a method oftreating a subject suffering from or diagnosed with a disease, disorder,or medical condition mediated by a prolyl hydroxylase enzyme activity,comprising administering to the subject in need of such treatment aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable prodrug, orpharmaceutically active metabolite thereof.

In certain preferred embodiments of the inventive method, the disease,disorder, or medical condition is selected from: anemia, vasculardisorders, metabolic disorders, and wound healing.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

DETAILED DESCRIPTION

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. For the sake of brevity, the disclosures of thepublications, including patents, cited in this specification are hereinincorporated by reference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which also may be structurally depicted by thesymbol, “i”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples.

The term “perhaloalkyl” refers to a straight- or branched-chain alkylgroup having from 1 to 12 carbon atoms in the chain optionallysubstituting hydrogens with halogens. Examples of perhaloalkyl groupsinclude trifluoromethyl (CF₃), difluoromethyl (CF₂H), monofluoromethyl(CH₂F), pentafluoroethyl (CF₂CF₃), tetrafluoroethyl (CHFCF₃),trifluoroethyl (CH₂CF₃), and groups that in light of the ordinary skillin the art and the teachings provided herein would be consideredequivalent to any one of the foregoing examples.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

A “heterocycloalkyl” refers to a monocyclic ring structure that issaturated or partially saturated and has from 4 to 7 ring atoms per ringstructure selected from carbon atoms and up to two heteroatoms selectedfrom nitrogen, oxygen, and sulfur. The ring structure may optionallycontain up to two oxo groups on sulfur ring members. Illustrativeentities, in the form of properly bonded moieties, include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of cycloalkyl,heterocycloalkyl, and heteroaryl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. In cases where a specifiedmoiety or group is not expressly noted as being optionally substitutedor substituted with any specified substituent, it is understood thatsuch a moiety or group is intended to be unsubstituted.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.Additionally, any formula given herein is intended to embrace hydrates,solvates, and polymorphs of such compounds, and mixtures thereof.

Additionally, any formula given herein is intended to refer also tohydrates, solvates, and polymorphs of such compounds, and mixturesthereof, even if such forms are not listed explicitly. Certain compoundsof Formula (I) or pharmaceutically acceptable salts of compounds ofFormula (I) may be obtained as solvates. Solvates include those formedfrom the interaction or complexation of compounds of the invention withone or more solvents, either in solution or as a solid or crystallineform. In some embodiments, the solvent is water and then the solvatesare hydrates. In addition, certain crystalline forms of compounds ofFormula (I) or pharmaceutically acceptable salts of compounds of Formula(I) may be obtained as co-crystals. In certain embodiments of theinvention, compounds of Formula (I) were obtained in a crystalline form.In other embodiments, crystalline forms of compounds of Formula (I) werecubic in nature. In other embodiments, pharmaceutically acceptable saltsof compounds of Formula (I) were obtained in a crystalline form. Instill other embodiments, compounds of Formula (I) were obtained in oneof several polymorphic forms, as a mixture of crystalline forms, as apolymorphic form, or as an amorphous form. In other embodiments,compounds of Formula (I) convert in solution between one or morecrystalline forms and/or polymorphic forms.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Reference to a chemical entity herein stands for a reference to any oneof: (a) the actually recited form of such chemical entity, and (b) anyof the forms of such chemical entity in the medium in which the compoundis being considered when named. For example, reference herein to acompound such as R—COOH, encompasses reference to any one of, forexample, R—COOH_((s)), R—COOH_((sol)), and R—COO⁻ _((sol)). In thisexample, R—COOH_((s)) refers to the solid compound, as it could be forexample in a tablet or some other solid pharmaceutical composition orpreparation; R—COOH_((sol)) refers to the undissociated form of thecompound in a solvent; and R—COO⁻ _((sol)) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO⁻ upon dissociation in the medium being considered. Inanother example, an expression such as “exposing an entity to compoundof formula R—COOH” refers to the exposure of such entity to the form, orforms, of the compound R—COOH that exists, or exist, in the medium inwhich such exposure takes place. In still another example, an expressionsuch as “reacting an entity with a compound of formula R—COOH” refers tothe reacting of (a) such entity in the chemically relevant form, orforms, of such entity that exists, or exist, in the medium in which suchreacting takes place, with (b) the chemically relevant form, or forms,of the compound R—COOH that exists, or exist, in the medium in whichsuch reacting takes place. In this regard, if such entity is for examplein an aqueous environment, it is understood that the compound R—COOH isin such same medium, and therefore the entity is being exposed tospecies such as R—COOH_((aq)) and/or R—COO⁻ _((aq)), where the subscript“(aq)” stands for “aqueous” according to its conventional meaning inchemistry and biochemistry. A carboxylic acid functional group has beenchosen in these nomenclature examples; this choice is not intended,however, as a limitation but it is merely an illustration. It isunderstood that analogous examples can be provided in terms of otherfunctional groups, including but not limited to hydroxyl, basic nitrogenmembers, such as those in amines, and any other group that interacts ortransforms according to known manners in the medium that contains thecompound. Such interactions and transformations include, but are notlimited to, dissociation, association, tautomerism, solvolysis,including hydrolysis, solvation, including hydration, protonation, anddeprotonation.

In another example, a zwitterionic compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Inerest (ChEBI) dictionary of molecular entities. Asgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds,inner salts and dipolar ions in the known and well established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl,¹²⁵I, respectively. Such isotopically labeled compounds are useful inmetabolic studies (preferably with ¹⁴C), reaction kinetic studies (with,for example ²H or ³H), detection or imaging techniques [such as positronemission tomography (PET) or single-photon emission computed tomography(SPECT)] including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or SPECT studies.Further, substitution with heavier isotopes such as deuterium (i.e., ²H)may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R³, A, X⁴, X⁵, X⁶, X⁷, R^(a), R^(b), R^(c), R^(d), and R^(e), andany other generic substituent symbol used herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof.

By way of a second example on substituent terminology, if it is hereindescribed that substituent S_(example) is one of S₁, S₂, and S₃, thislisting refers to embodiments of this invention for which S_(example) isS₁; S_(example) is S₂; S_(example) is S₃; S_(example) is one of S₁ andS₂; S_(example) is one of S₁ and S₃; S_(example) is one of S₂ and S₃;S_(example) is one of S₁, S₂ and S₃; and S_(example) is any equivalentof each one of these choices. The shorter terminology “S_(example) isone of S₁, S₂, and S₃” is accordingly used herein for the sake ofbrevity, but not by way of limitation. The foregoing second example onsubstituent terminology, which is stated in generic terms, is meant toillustrate the various substituent assignments described herein. Theforegoing convention given herein for substituents extends, whenapplicable, to members such as R¹, R², R³, A, X⁴, X⁵, X⁶, X⁷, R^(a),R^(b), R^(c), R^(d), and R^(e), and any other generic substituent symbolused herein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≤N≤m, with m>n.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B-, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the secondsubstituted member and B attached to the first substituted member.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

Chemical depictions are intended to portray the compound portionscontaining the orientations as written.

The present invention is generally directed to compounds of formula (I),

the use of compounds of Formula (I) and pharmaceutical compositionscontaining such compounds thereof to treat patients (humans or othermammals) with disorders related to the modulation of the prolylhydroxylase enzyme. The instant invention also includes methods ofmaking such a compound, pharmaceutical composition, pharmaceuticallyacceptable salt, pharmaceutically acceptable prodrug, andpharmaceutically active metabolites thereof.

In one preferred embodiment for Formula (I), each of R² and R³ are H.

In another embodiment of Formula (I), Z is C.

In related embodiments for Formula (I), n is 4, and each R¹ isindependently H, halo, hydroxyl, alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkyl sulfone, optionally substituted 3-8 membered aliphaticor aromatic or heterocyclic ring, amino, alkylamino, alkyl sulfonamide,aryl sulfonamide, nitro, cyano, substituted phenoxy, benzyloxy,substituted aryl sulfone, substituted aryl sulfoxide, substituted arylsulfonyl, substituted benzyl sulfone, substituted benzyl sulfoxide,substituted benzyl sulfonyl or substituted phenylsulfamoyl.

R¹ can also independently be H, halo, straight- or branched-chainC₁₋₄alkyl, straight- or branched-chain C₁₋₄triflouroalkoxy, straight- orbranched-chain C₁₋₄perhaloalkyl, or monocyclic C₃₋₈carbocycle saturatedor partially saturated.

In another preferred embodiment, two adjacent R¹ groups may be joined toform an optionally substituted 3-8 member saturated or unsaturatedcarbocyclic or heterocyclic ring.

In other preferred embodiments for Formula (I), each R¹ is independentlyselected from the group consisting of hydrogen, —Cl, —F, —Br, —I,—C₁₋₄alkyl, —CF₃, —C₃₋₈cycloalkyl, —SC₁₋₄alkyl, —S(O)C₁₋₄alkyl,—S(O)₂C₁₋₄alkyl, —OCF₃, —OC₁₋₄alkyl, —CN, —NO₂, —NH₂, —NH—C₁₋₄alkyl,pyrrolidino, piperidino, morpholino, —CO₂H, —NHS(O)₂C₁₋₄alkyl, and—NH—C(O)C₁₋₄alkyl, phenyl, benzyl, phenoxy and benzyloxy.

In preferred embodiments of Formula (I), R¹ is H, 5,6-dichloro,5-trifluoromethyl, 5-chloro-6-fluoro, 5,6-dimethyl, 5-bromo, 5-methoxy,4-chloro-6-trifluoromethyl, 5,6-dimethoxy, 4,5-dimethyl,5-trifluoromethoxy, 5-bromo, 5,6-dichloro, 5-bromo, 5,6-dichloro,5-chloro, 5-bromo-6,7-dimethyl, 4-chloro, 5-chloro-7-trifluoromethyl,7-bromo-5-trifluoromethoxy, 6-chloro-5-trifluoromethyl, 4,5,6-trifluoro,4-bromo-5,6-difluoro, 6-chloro-4-methyl, 4,6-dichloro,4-bromo-6-trifluoromethyl, 5,6-difluoro, 4-bromo-6-chloro,6-methanesulfonyl, 5-chloro-6-cyano, 6-chloro-5-nitro, 5-amino-6-chloro,5-fluoro, 6-chloro-5-pyrrolidin-1-yl, 6-chloro-5-piperidin-1-yl,6-chloro-5-morpholin-4-yl, 6-chloro-5-methoxy, 4-carboxy,5-bromo-7-fluoro, 5-bromo-7-methyl, 6-methylsulfanyl-5-trifluoromethyl,6-propylsulfanyl-5-trifluoromethyl,6-isopropylsulfanyl-5-trifluoromethyl, 5-fluoro-6-methylsulfanyl,5-chloro-6-methylsulfanyl, 5-chloro-6-ethylsulfanyl,5-chloro-6-isopropylsulfanyl, 5-chloro-6-propylsulfanyl,6-methylsulfanyl-5-trifluoromethoxy,6-isopropylsulfanyl-5-trifluoromethoxy,6-propylsulfanyl-5-trifluoromethoxy, 5-chloro-6-ethanesulfinyl,5-chloro-6-ethanesulfonyl, 6-methanesulfonyl-5-trifluoromethyl,5-fluoro-6-methanesulfonyl, 5-chloro-6-methanesulfonyl,6-methanesulfonyl-5-trifluoromethoxy, 5-chloro-6-(propane-2-sulfonyl),5-chloro-6-(propane-1-sulfonyl),6-(propane-2-sulfonyl)-5-trifluoromethyl,6-(propane-1-sulfonyl)-5-trifluoromethyl,6-[(1-methylethyl)sulfonyl]-5-(trifluoromethoxy,6-(propane-2-sulfonyl)-5-trifluoromethoxy,6-(methylsulfinyl)-5-(trifluoromethyl, 6-bromo-5-fluoro, 4-fluoro,4,5-difluoro, 4,6-difluoro, 6-chloro-5-trifluoromethoxy,5-fluoro-4-methyl, 5-piperidin-1-yl-6-(trifluoromethoxy,5-fluoro-6-piperidin-1-yl, 6-ethoxy-5-fluoro, 4-bromo-6-fluoro,5,6-bis-trifluoromethyl, 4,5,6-trichloro, 4-bromo-5,6-dichloro,6-fluoro-5-trifluoromethyl, 6-chloro-5-ethylamino,6-chloro-5-propylamino, 6-chloro-5-cyclopropanesulfonylamino,6-chloro-5-methanesulfonylamino, 6-chloro-5-ethanesulfonylamino,5-acetylamino-6-chloro, 6-chloro-5-propionylamino,5-ethylsulfanyl-6-trifluoromethyl, 5-ethylsulfanyl-6-trifluoromethoxy,5-ethylsulfanyl-6-fluoro, 6-fluoro-5-propylsulfanyl,6-fluoro-5-isopropylsulfanyl, 5-ethylsulfonyl-6-trifluoromethyl,5-ethylsulfonyl-6-trifluoromethoxy, 5-ethylsulfonyl-6-fluoro,6-fluoro-5-propylsulfonyl, and 6-fluoro-5-isopropylsulfonyl.

In preferred embodiments of Formula (I), where each R¹ is independentlyselected from the group consisting of H, 3-(3-chloro-benzyloxy)-phenyl,3-(2-chloro-benzyloxy)-phenyl, 3-(4-chloro-benzyloxy)-phenyl,3-benzyloxy-phenyl, 4-benzyloxy-phenyl, 3-trifluoromethyl-phenyl,3,4-dichlorophenyl, 4-hydroxyphenyl, 3-hydroxyphenyl,3,4-dichloro-phenoxy)-6-trifluoromethyl, 6-chloro-5-(4-chloro-phenoxy),(4-chloro-phenoxy)-6-trifluoromethoxy, 5-phenoxy-6-trifluoromethoxy,4-fluoro-phenoxy)-6-trifluoromethyl,(4-chloro-phenoxy)-6-trifluoromethyl, 5-phenoxy-6-trifluoromethyl,6-chloro-5-phenoxy, 5-benzyloxy-6-chloro, 6-chloro-5-m-tolylsulfanyl,6-chloro-5-(4-chloro-phenylsulfanyl, 6-chloro-5-phenylsulfanyl,6-chloro-5-(3,4-dichloro-phenylsulfanyl,6-chloro-5-(3-methoxy-phenylsulfanyl,6-chloro-5-(4-methoxy-phenylsulfanyl), 5-benzylsulfanyl-6-chloro,4-tert-butyl-benzylsulfanyl)-6-chloro,6-chloro-5-(4-fluoro-benzylsulfanyl,6-chloro-5-(2-chloro-benzylsulfanyl, 6-chloro-5-phenethylsulfanyl,6-chloro-5-(toluene-3-sulfonyl, 5-benzenesulfonyl-6-chloro,6-chloro-5-(4-methoxy-benzenesulfonyl,6-chloro-5-(4-chloro-benzenesulfonyl,6-chloro-5-(4-trifluoromethoxy-benzenesulfonyl,6-chloro-5-(3,4-dichloro-benzenesulfonyl,6-chloro-5-(3-methoxy-benzenesulfonyl, 6-chloro-5-phenylmethanesulfonyl,6-chloro-5-(2,4,6-trimethyl-phenylmethanesulfonyl,6-chloro-5-(4-methoxy-phenylmethanesulfonyl,chloro-5-(4-fluoro-phenylmethanesulfonyl,6-chloro-5-(2-chloro-phenylmethanesulfonyl,6-chloro-5-(2-phenyl-ethanesulfonyl, 5-benzenesulfinyl-6-chloro,5-phenylcarbamoyl, 5-benzylcarbamoyl, 5-(morpholin-4-ylcarbamoyl),5-benzyloxymethyl, 5-benzylamino, 6-chloro-5-phenylamino,6-chloro-5-(2-morpholin-4-yl-ethylamino),5-benzenesulfonylamino-6-chloro, 5-benzoylamino-6-chloro,6-chloro-5-(2-morpholin-4-yl-acetylamino),6-chloro-5-(2-piperidin-1-yl-acetylamino),6-chloro-5-[2-(4-methyl-piperazin-1-yl, 6-chloro-5-(4-methoxy-phenoxy),6-chloro-5-(4-chloro-2-fluoro-phenoxy),6-chloro-5-(4-trifluoromethoxy-phenoxy),6-chloro-5-(3-chloro-4-fluoro-phenoxy),5-phenylsulfanyl-6-trifluoromethyl,5-(4-methoxy-phenylsulfanyl)-6-trifluoromethyl,5-benzenesulfonyl-6-trifluoromethyl,5-(4-methoxy-benzenesulfonyl)-6-trifluoromethyl,6-chloro-5-(4-chloro-benzylsulfanyl,6-chloro-5-(3-chloro-benzylsulfanyl),6-chloro-5-cyclohexylmethylsulfanyl,6-chloro-5-(2-morpholin-4-yl-ethylsulfanyl),-chloro-5-(3,4-dichloro-benzylsulfanyl,6-chloro-5-(2,6-dichloro-benzylsulfanyl),6-chloro-5-(4-methyl-benzylsulfanyl),6-chloro-5-(4-trifluoromethyl-benzylsulfanyl),5-(2,4-bis-trifluoromethyl-benzylsulfanyl)-6-chloro,6-chloro-5-(2′-cyano-biphenyl-4-ylmethylsulfanyl),6-chloro-5-(4-chloro-phenylmethanesulfonyl),6-chloro-5-(3-chloro-phenylmethanesulfonyl),chloro-5-cyclohexylmethanesulfonyl,6-chloro-5-(3,4-dichloro-phenylmethanesulfonyl),6-chloro-5-(2,6-dichloro-phenylmethanesulfonyl),chloro-5-p-tolylmethanesulfonyl,6-chloro-5-(4-trifluoromethyl-phenylmethanesulfonyl),5-(2,4-bis-trifluoromethyl-benzylsulfanyl),chloro-5-(2′-cyano-biphenyl-4-ylmethanesulfonyl and6-chloro-5-phenylsulfamoyl.

Exemplary compounds of the present invention are set forth in the Tablebelow.

Enzyme Cellular % EPO Ex. Chemical Name pIC50 Stimulation 11-(1H-Benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic 6.1 7.1 acid; 21-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4- 6.9 151.91carboxylic acid; 3 1-(5-Trifluoromethyl-1H-benzoimidazol-2-yl)-1H- 6.6109.74 pyrazole-4-carboxylic acid; 41-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-1H- 6.7 132.79pyrazole-4-carboxylic acid; 51-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4- 6.1 2.1 carboxylicacid; 6 1-(5-Bromo-1H-benzoimidazol-2-yl)-1H-pyrazole-4- 6.4 9.91carboxylic acid; 7 1-(5-Methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-6.4 16.8 carboxylic acid; 81-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)- 6.8 20.971H-pyrazole-4-carboxylic acid; 91-(5,6-Dimethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole- 6.4 4.264-carboxylic acid; 101-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4- 5.1 10.7carboxylic acid; 11 1-(5-Trifluoromethoxy-1H-benzoimidazol-2-yl)-1H- 6.5123.68 pyrazole-4-carboxylic acid; 121-{5-[3-(3-Chloro-benzyloxy)-phenyl]-1H-benzoimidazol- 7.5 8.762-yl}-1H-pyrazole-4-carboxylic acid; 131-{5-[3-(2-Chloro-benzyloxy)-phenyl]-1H-benzoimidazol- 7.6 182-yl}-1H-pyrazole-4-carboxylic acid; 141-{5-[3-(4-Chloro-benzyloxy)-phenyl]-1H-benzoimidazol- 7.4 20.152-yl}-1H-pyrazole-4-carboxylic acid; 151-[5-(3-Benzyloxy-phenyl)-1H-benzoimidazol-2-yl]-1H- 7.3 10.77pyrazole-4-carboxylic acid; 161-[5-(4-Benzyloxy-phenyl)-1H-benzoimidazol-2-yl]-1H- 6.7 6.97pyrazole-4-carboxylic acid; 171-[5-(3-Trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]- 7.1 5.81H-pyrazole-4-carboxylic acid; 181-[5-(3,4-Dichloro-phenyl)-1H-benzoimidazol-2-yl]-1H- 7.1 15.3pyrazole-4-carboxylic acid; 191-(5-Bromo-1H-benzoimidazol-2-yl)-3-trifluoromethyl- <4 20.521H-pyrazole-4-carboxylic acid; 201-(5,6-dichloro-1H-benzoimidazol-2-yl)-3-trifluoromethyl- <4 18.811H-pyrazole-4-carboxylic acid; 211-(5-Bromo-1H-benzoimidazol-2-yl)-3,5-dimethyl-1H- 4.2 7.24pyrazole-4-carboxylic acid; 221-(5,6-Dichloro-1H-benzoimidazol-2-yl)-3,5-dimethyl-1H- <4 0.47pyrazole-4-carboxylic acid; 231-[5-(4-Hydroxy-phenyl)-1H-benzoimidazol-2-yl]-1H- 6.6 6.49pyrazole-4-carboxylic acid; 241-[5-(3-Hydroxy-phenyl)-1H-benzoimidazol-2-yl]-1H- 6.5 11.15pyrazole-4-carboxylic acid; 251-(5-Chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4- 6.3 71.87 carboxylicacid; 26 1-(5-Bromo-6,7-dimethyl-1H-benzoimidazol-2-yl)-1H- 6.4 11.9pyrazole-4-carboxylic acid; 271-(4-Chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4- 6.1 19.12 carboxylicacid; 28 1-(5-Chloro-7-trifluoromethyl-1H-benzoimidazol-2-yl)- 6.4 16.61H-pyrazole-4-carboxylic acid; 291-(7-Bromo-5-trifluoromethoxy-1H-benzoimidazol-2-yl)- 6.8 57.551H-pyrazole-4-carboxylic acid; 301-(6-Chloro-5-trifluoromethyl-1H-benzoimidazol-2-yl)- 7.14 128.941H-pyrazole-4-carboxylic acid; 311-(4,5,6-Trifluoro-1H-benzoimidazol-2-yl)-1H-pyrazole- 7 18.24-carboxylic acid; 32 1-(4-Bromo-5,6-difluoro-1H-benzoimidazol-2-yl)-1H-6.7 33 pyrazole-4-carboxylic acid; 331-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-1H- 6 13.4pyrazole-4-carboxylic acid; 341-(4,6-Dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4- 6.5 56.3carboxylic acid; 35 1-(4-Bromo-6-trifluoromethyl-1H-benzoimidazol-2-yl)-6.8 29.7 1H-pyrazole-4-carboxylic acid; 361-(5,6-Difluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4- 6.6 79.4carboxylic acid; 37 1-(4-Bromo-6-chloro-1H-benzoimidazol-2-yl)-1H- 6.634.03 pyrazole-4-carboxylic acid; 381-(6-Methanesulfonyl-1H-benzoimidazol-2-yl)-1H- 7.1 40.93pyrazole-4-carboxylic acid; 391-(6-Chloro-5-cyano-1H-benzoimidazol-2-yl)-1H- 7.4 29.93pyrazole-4-carboxylic acid; 401-(6-Chloro-5-nitro-1H-benzoimidazol-2-yl)-1H-pyrazole- 7.5 93.444-carboxylic acid; 41 1-(5-Amino-6-chloro-1H-benzoimidazol-2-yl)-1H- 6.430 pyrazole-4-carboxylic acid; 421-(5-Fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4- 6.3 33.76 carboxylicacid; 43 1-(6-Chloro-5-pyrrolidin-1-yl-1H-benzoimidazol-2-yl)-1H- 6.7177.5 pyrazole-4-carboxylic acid; 441-(6-Chloro-5-piperidin-1-yl-1H-benzoimidazol-2-yl)-1H- 6.7 138.8pyrazole-4-carboxylic acid; 451-(6-Chloro-5-morpholin-4-yl-1H-benzoimidazol-2-yl)- 6.6 30.851H-pyrazole-4-carboxylic acid; 461-(6-Chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H- 6.5 76pyrazole-4-carboxylic acid; 472-(4-Carboxy-pyrazol-1-yl)-1H-benzoimidazole-5- 6.6 11 carboxylic acid;48 1-(5-Bromo-7-fluoro-1H-benzoimidazol-2-yl)-1H- 6.3 44pyrazole-4-carboxylic acid; 491-(5-Bromo-7-methyl-1H-benzoimidazol-2-yl)-1H- 6.1 24pyrazole-4-carboxylic acid; 501-[5-(3,4-Dichloro-phenoxy)-6-trifluoromethyl-1H- 7.4 17.98benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 511-[6-Chloro-5-(4-chloro-phenoxy)-1H-benzoimidazol-2- 7.4 150.4yl]-1H-pyrazole-4-carboxylic acid; 521-[5-(4-Chloro-phenoxy)-6-trifluoromethoxy-1H- 7.4 21.55benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 531-(5-Phenoxy-6-trifluoromethoxy-1H-benzoimidazol-2- 7.2 137.71yl)-1H-pyrazole-4-carboxylic acid; 541-[5-(4-Fluoro-phenoxy)-6-trifluoromethyl-1H- 7.3 75.52benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 551-[5-(4-Chloro-phenoxy)-6-trifluoromethyl-1H- 7.5 44.23benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 561-(5-Phenoxy-6-trifluoromethyl-1H-benzoimidazol-2-yl)- 7.2 142.551H-pyrazole-4-carboxylic acid; 571-(6-Chloro-5-phenoxy-1H-benzoimidazol-2-yl)-1H- 6.9 55pyrazole-4-carboxylic acid; 581-(5-Bromo-7-methyl-1H-imidazo[4,5-f]quinolin-2-yl)-1H- 7.2 50pyrazole-4-carboxylic acid; 591-(5-Benzyloxy-6-chloro-1H-benzoimidazol-2-yl)-1H- 6.4 55.9pyrazole-4-carboxylic acid; 601-(6-Chloro-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl)- 6.9 42.301H-pyrazole-4-carboxylic acid; 611-[6-Chloro-5-(4-chloro-phenylsulfanyl)-1H- 7.07 101.2benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 621-(6-Chloro-5-phenylsulfanyl-1H-benzoimidazol-2-yl)- 6.75 45.841H-pyrazole-4-carboxylic acid; 631-[6-Chloro-5-(3,4-dichloro-phenylsulfanyl)-1H- 6.18 26.54benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 641-[6-Chloro-5-(3-methoxy-phenylsulfanyl)-1H- 6.9 38.26benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 651-[6-Chloro-5-(4-methoxy-phenylsulfanyl)-1H- 6.6 56.3benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 661-(5-Benzylsulfanyl-6-chloro-1H-benzoimidazol-2-yl)- 6.7 41.641H-pyrazole-4-carboxylic acid; 671-[5-(4-tert-Butyl-benzylsulfanyl)-6-chloro-1H- 7.2 11.72benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 681-[6-Chloro-5-(4-fluoro-benzylsulfanyl)-1H- 6.8 58.37benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 691-[6-Chloro-5-(2-chloro-benzylsulfanyl)-1H- 6.8 85.3benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 701-(6-Chloro-5-phenethylsulfanyl-1H-benzoimidazol-2-yl)- 6.7 74.241H-pyrazole-4-carboxylic acid; 711-(6-Methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol- 7.1 113.952-yl)-1H-pyrazole-4-carboxylic acid; 721-(6-Propylsulfanyl-5-trifluoromethyl-1H-benzoimidazol- 7.1 NT2-yl)-1H-pyrazole-4-carboxylic acid; 731-(6-Isopropylsulfanyl-5-trifluoromethyl-1H- 7.2 NTbenzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; 741-(5-Fluoro-6-methylsulfanyl-1H-benzoimidazol-2-yl)- 6.9 77.7951H-pyrazole-4-carboxylic acid; 751-(5-Chloro-6-methylsulfanyl-1H-benzoimidazol-2-yl)- 7 106.171H-pyrazole-4-carboxylic acid; 761-(5-Chloro-6-ethylsulfanyl-1H-benzoimidazol-2-yl)-1H- 6.9 211.75pyrazole-4-carboxylic acid; 771-(5-Chloro-6-isopropylsulfanyl-1H-benzoimidazol-2-yl)- 6.8 152.891H-pyrazole-4-carboxylic acid; 781-(5-Chloro-6-propylsulfanyl-1H-benzoimidazol-2-yl)-1H- 7 125.21pyrazole-4-carboxylic acid; 791-(6-Methylsulfanyl-5-trifluoromethoxy-1H- 7.1 83.83benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; 801-(6-Isopropylsulfanyl-5-trifluoromethoxy-1H- 7 NTbenzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; 811-(6-Propylsulfanyl-5-trifluoromethoxy-1H- 7 NTbenzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; 821-[6-Chloro-5-(toluene-3-sulfonyl)-1H-benzoimidazol-2- 7.4 85.32yl]-1H-pyrazole-4-carboxylic acid; 831-(5-Benzenesulfonyl-6-chloro-1H-benzoimidazol-2-yl)- 7.57 96.651H-pyrazole-4-carboxylic acid; 841-[6-Chloro-5-(4-methoxy-benzenesulfonyl)-1H- 7.3 42.71benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 851-[6-Chloro-5-(4-chloro-benzenesulfonyl)-1H- 7.3 51.64benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 861-[6-Chloro-5-(4-trifluoromethoxy-benzenesulfonyl)-1H- 7.3 48.9benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 871-[6-Chloro-5-(3,4-dichloro-benzenesulfonyl)-1H- 6.68 32.39benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 881-[6-Chloro-5-(3-methoxy-benzenesulfonyl)-1H- 7.4 69.43benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 891-(6-Chloro-5-phenylmethanesulfonyl-1H- 7.5 28.45benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; 901-[6-Chloro-5-(2,4,6-trimethyl-phenylmethanesulfonyl)- 7.3 8.251H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 911-[6-Chloro-5-(4-methoxy-phenylmethanesulfonyl)-1H- 7.7 22.01benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 921-[6-Chloro-5-(4-fluoro-phenylmethanesulfonyl)-1H- 7.5 61.2benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 931-[6-Chloro-5-(2-chloro-phenylmethanesulfonyl)-1H- 7.5 78.5benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 941-[6-Chloro-5-(2-phenyl-ethanesulfonyl)-1H- 7.4 65.1benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 951-(5-Chloro-6-ethanesulfinyl-1H-benzoimidazol-2-yl)-1H- 7.2 46.3pyrazole-4-carboxylic acid; 961-(5-Chloro-6-ethanesulfonyl-1H-benzoimidazol-2-yl)- 7.4 671H-pyrazole-4-carboxylic acid; 971-(6-Methanesulfonyl-5-trifluoromethyl-1H- 7.6 75.88benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; 981-(5-Fluoro-6-methanesulfonyl-1H-benzoimidazol-2-yl)- 7.3 41.371H-pyrazole-4-carboxylic acid; 991-(5-Chloro-6-methanesulfonyl-1H-benzoimidazol-2-yl)- 7.4 34.851H-pyrazole-4-carboxylic acid; 1001-(6-Methanesulfonyl-5-trifluoromethoxy-1H- 7.5 50.16benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; 1011-[5-Chloro-6-(propane-2-sulfonyl)-1H-benzoimidazol-2- 7.3 62.2yl]-1H-pyrazole-4-carboxylic acid; 1021-[5-Chloro-6-(propane-1-sulfonyl)-1H-benzoimidazol-2- 7.5 54.94yl]-1H-pyrazole-4-carboxylic acid; 1031-[6-(Propane-2-sulfonyl)-5-trifluoromethyl-1H- 7.4 NTbenzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1041-[6-(Propane-1-sulfonyl)-5-trifluoromethyl-1H- 7.5 NTbenzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1051-[6-(Propane-2-sulfonyl)-5-trifluoromethoxy-1H- 7.4 NTbenzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1061-[6-(Propane-1-sulfonyl)-5-trifluoromethoxy-1H- 7.5 123.7benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1071-(5-Benzenesulfinyl-6-chloro-1H-benzoimidazol-2-yl)- 7.2 47.571H-pyrazole-4-carboxylic acid; 1081-(6-Methanesulfinyl-5-trifluoromethyl-1H- 7.3 20.41benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; 1091-(6-Bromo-5-fluoro-1H-benzoimidazol-2-yl)-1H- 6.7 99pyrazole-4-carboxylic acid; 1101-(4-Fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4- 6.2 45.87 carboxylicacid; 111 1-(4,5-Difluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4- 6.632.58 carboxylic acid; 1121-(4,6-Difluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4- 6.8 31.96carboxylic acid; 1131-(6-Chloro-5-trifluoromethoxy-1H-benzoimidazol-2-yl)- 6.98 109.331H-pyrazole-4-carboxylic acid; 1141-(1H-Naphtho[2,3-d]imidazol-2-yl)-1H-pyrazole-4- 6.3 144.2 carboxylicacid; 115 1-(3H-Naphtho[1,2-d]imidazol-2-yl)-1H-pyrazole-4- 6.1 50carboxylic acid; 116 1-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-1H- 5.818.3 pyrazole-4-carboxylic acid; 1171-(5-Piperidin-1-yl-6-trifluoromethoxy-1H-benzoimidazol- 6.5 802-yl)-1H-pyrazole-4-carboxylic acid 1181-(5-Fluoro-6-piperidin-1-yl-1H-benzoimidazol-2-yl)-1H- 6.8 152pyrazole-4-carboxylic acid; 1191-(6-Ethoxy-5-fluoro-1H-benzoimidazol-2-yl)-1H- 6.5 69pyrazole-4-carboxylic acid; 1201-(5-Phenylcarbamoyl-1H-benzoimidazol-2-yl)-1H- 6.9 21.15pyrazole-4-carboxylic acid; 1211-(5-Benzylcarbamoyl-1H-benzoimidazol-2-yl)-1H- 7.1 18.5pyrazole-4-carboxylic acid; 1221-[5-(Morpholin-4-ylcarbamoyl)-1H-benzoimidazol-2-yl]- 6.6 5.41H-pyrazole-4-carboxylic acid; 1231-(5-Benzyloxymethyl-1H-benzoimidazol-2-yl)-1H- 6.3 61.15pyrazole-4-carboxylic acid; 1241-(4-Bromo-6-fluoro-1H-benzoimidazol-2-yl)-1H- 6.3 2.4pyrazole-4-carboxylic acid; 1251-(8H-Imidazo[4′,5′:3,4]benzo[2,1-d]thiazol-7-yl)-1H- 6 46.75pyrazole-4-carboxylic acid; 1261-(5,6-Bis-trifluoromethyl-1H-benzoimidazol-2-yl)-1H- 7.4 82.65pyrazole-4-carboxylic acid; 1271-(4,5,6-Trichloro-1H-benzoimidazol-2-yl)-1H-pyrazole- 6.9 70.64-carboxylic acid; 1281-(4-Bromo-5,6-dichloro-1H-benzoimidazol-2-yl)-1H- 7.1 24.1pyrazole-4-carboxylic acid; 1291-(6-Fluoro-5-trifluoromethyl-1H-benzoimidazol-2-yl)- 7 70.81H-pyrazole-4-carboxylic acid; 1301-(6-Chloro-5-ethylamino-1H-benzoimidazol-2-yl)-1H- 6.2 48pyrazole-4-carboxylic acid; 1311-(6-Chloro-5-propylamino-1H-benzoimidazol-2-yl)-1H- 6.5 89pyrazole-4-carboxylic acid; 1321-(5-Benzylamino-6-chloro-1H-benzoimidazol-2-yl)-1H- 6.2 52.6pyrazole-4-carboxylic acid; 1331-(6-Chloro-5-phenylamino-1H-benzoimidazol-2-yl)-1H- 6.9 77pyrazole-4-carboxylic acid; 1341-[6-Chloro-5-(2-morpholin-4-yl-ethylamino)-1H- 6.3 56.5benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1351-(6-Chloro-5-cyclopropanesulfonylamino-1H- 6.8 17benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; 1361-(6-Chloro-5-methanesulfonylamino-1H-benzoimidazol- 6.8 92-yl)-1H-pyrazole-4-carboxylic acid; 1371-(6-Chloro-5-ethanesulfonylamino-1H-benzoimidazol- 6.6 112-yl)-1H-pyrazole-4-carboxylic acid; 1381-(5-Benzenesulfonylamino-6-chloro-1H-benzoimidazol- 6.8 192-yl)-1H-pyrazole-4-carboxylic acid; 1391-(5-Acetylamino-6-chloro-1H-benzoimidazol-2-yl)-1H- 6.3 24pyrazole-4-carboxylic acid; 1401-(6-Chloro-5-propionylamino-1H-benzoimidazol-2-yl)- 6.4 101H-pyrazole-4-carboxylic acid; 1411-(5-Benzoylamino-6-chloro-1H-benzoimidazol-2-yl)-1H- 6.6 33pyrazole-4-carboxylic acid; 1421-[6-Chloro-5-(2-morpholin-4-yl-acetylamino)-1H- 6.4 17benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1431-[6-Chloro-5-(2-piperidin-1-yl-acetylamino)-1H- 6.2 20benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1441-{6-Chloro-5[2-(4-methyl-piperazin-1-yl)-acetylamino]- 6.4 161H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid; 1451-[6-Chloro-5-(4-methoxy-phenoxy)-1H-benzoimidazol- 7.1 13.922-yl]-1H-pyrazole-4-carboxylic acid; 1461-[6-Chloro-5-(4-chloro-2-fluoro-phenoxy)-1H- 7.2 49.85benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1471-[6-Chloro-5-(4-trifluoromethoxy-phenoxy)-1H- 7.4 45.85benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1481-[6-Chloro-5-(3-chloro-4-fluoro-phenoxy)-1H- 7.1 38.12benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1491-(5-Ethylsulfanyl-6-trifluoromethyl-1H-benzoimidazol-2- 7.3 57.8yl)-1H-pyrazole-4-carboxylic acid; 1501-(5-Ethylsulfanyl-6-trifluoromethoxy-1H-benzoimidazol- 7.2 47.22-yl)-1H-pyrazole-4-carboxylic acid; 1511-(5-Ethylsulfanyl-6-fluoro-1H-benzoimidazol-2-yl)-1H- 6.9 106.61pyrazole-4-carboxylic acid; 1521-(6-Fluoro-5-propylsulfanyl-1H-benzoimidazol-2-yl)-1H- 6.9 91.38pyrazole-4-carboxylic acid; 1531-(6-Fluoro-5-isopropylsulfanyl-1H-benzoimidazol-2-yl)- 6.9 NT1H-pyrazole-4-carboxylic acid; 1541-(5-Ethylsulfonyl-6-trifluoromethyl-1H-benzoimidazol-2- 7.6 53.82yl)-1H-pyrazole-4-carboxylic acid; 1551-(5-Ethylsulfonyl-6-trifluoromethoxy-1H-benzoimidazol- 7.6 47.212-yl)-1H-pyrazole-4-carboxylic acid; 1561-(5-Ethylsulfonyl-6-fluoro-1H-benzoimidazol-2-yl)-1H- 7.4 51.9pyrazole-4-carboxylic acid; 1571-(6-Fluoro-5-propylsulfonyl-1H-benzoimidazol-2-yl)-1H- 7.4 NTpyrazole-4-carboxylic acid; 1581-(6-Fluoro-5-isopropylsulfonyl-1H-benzoimidazol-2-yl)- 7.3 NT1H-pyrazole-4-carboxylic acid; 1591-(5-Phenylsulfanyl-6-trifluoromethyl-1H-benzoimidazol- 7.4 11.012-yl)-1H-pyrazole-4-carboxylic acid; 1601-[5-(4-Methoxy-phenylsulfanyl)-6-trifluoromethyl-1H- 7.5 36.1benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1611-(5-Benzenesulfonyl-6-trifluoromethyl-1H- 7.6 98.15benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; 1621-[5-(4-Methoxy-benzenesulfonyl)-6-trifluoromethyl-1H- 7.6 45.8benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1631-[6-Chloro-5-(4-chloro-benzylsulfanyl)-1H- 6.5 36.98benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1641-[6-Chloro-5-(3-chloro-benzylsulfanyl)-1H- 6.6 27.4benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1651-(6-Chloro-5-cyclohexylmethylsulfanyl-1H- 6.9 27.3benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; 1661-[6-Chloro-5-(2-morpholin-4-yl-ethylsulfanyl)-1H- 7 15.1benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1671-[6-Chloro-5-(3,4-dichloro-benzylsulfanyl)-1H- 6.4 25.8benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1681-[6-Chloro-5-(2,6-dichloro-benzylsulfanyl)-1H- 7.3 50.14benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1691-[6-Chloro-5-(4-methyl-benzylsulfanyl)-1H- 6.7 NTbenzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1701-[6-Chloro-5-(4-trifluoromethyl-benzylsulfanyl)-1H- 6.7 NTbenzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1711-[5-(2,4-Bis-trifluoromethyl-benzylsulfanyl)-6-chloro-1H- 6.7 NTbenzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1721-[6-Chloro-5-(2′-cyano-biphenyl-4-ylmethylsulfanyl)-1H- 7.5 NTbenzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1731-[6-Chloro-5-(4-chloro-phenylmethanesulfonyl)-1H- 7.8 60.41benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1741-[6-Chloro-5-(3-chloro-phenylmethanesulfonyl)-1H- 7.6 40.9benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1751-(6-Chloro-5-cyclohexylmethanesulfonyl-1H- 7.7 48.7benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; 1761-[6-Chloro-5-(3,4-dichloro-phenylmethanesulfonyl)-1H- 7.6 44.23benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1771-[6-Chloro-5-(2,6-dichloro-phenylmethanesulfonyl)-1H- 7.5 66.6benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1781-(6-Chloro-5-p-tolylmethanesulfonyl-1H-benzoimidazol- 7.7 NT2-yl)-1H-pyrazole-4-carboxylic acid; 1791-[6-Chloro-5-(4-trifluoromethyl-phenylmethanesulfonyly 7.7 NT1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1801-[5-(2,4-Bis-trifluoromethyl-phenylmethanesulfonyl)-6- 7.6 NTchloro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1811-[6-Chloro-5-(2′-cyano-biphenyl-4-ylmethanesulfonyl)- 7.7 NT1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid; 1821-(1H-Imidazo[4,5-b]quinoxalin-2-yl)-1H-pyrazole-4- 5.5 13.4 carboxylicacid; 183 1-(6,7-Dichloro-1H-imidazo[4,5-b]quinoxalin-2-yl)-1H- 6.4 3.3pyrazole-4-carboxylic acid; 1841-(1H-Imidazo[4,5-b]pyrazin-2-yl)-1H-pyrazole-4- 5.9 8.3 carboxylicacid; 185 1-(6-Chloro-9H-purin-8-yl)-1H-pyrazole-4-carboxylic 5.3 11.7acid and 186 1-(6-Chloro-5-phenylsulfamoyl-1H-benzoimidazol-2-yl)- 7.439.1 1H-pyrazole-4-carboxylic acid.

The invention also includes pharmaceutically acceptable salts of thecompounds of Formula (I), preferably of those described above and of thespecific compounds exemplified herein, and methods of treatment usingsuch salts.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, G. S. Paulekuhn, etal., “Trends in Active Pharmaceutical Ingredient Salt Selection based onAnalysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72,S. M. Berge, et al., “Pharmaceutical Salts”, J Pharm Sci., 1977,66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection,and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.Examples of pharmaceutically acceptable salts are those that arepharmacologically effective and suitable for contact with the tissues ofpatients without undue toxicity, irritation, or allergic response. Acompound of Formula (I) may possess a sufficiently acidic group, asufficiently basic group, or both types of functional groups, andaccordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

When the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid, glutaric acid or glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

When the compound of Formula (I) is an acid, such as a carboxylic acidor sulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as N-methyl-D-glucamine, lysine,choline, glycine and arginine, ammonia, carbonates, bicarbonates,primary, secondary, and tertiary amines, and cyclic amines, such astromethamine, benzylamines, pyrrolidines, piperidine, morpholine, andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula (I), and treatment methods employing suchpharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formula (I)). A “pharmaceuticallyacceptable prodrug” is a prodrug that is non-toxic, biologicallytolerable, and otherwise biologically suitable for administration to thesubject. Illustrative procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985.

Exemplary prodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Fleisher et al., Adv. Drug DeliveryRev. 1996, 19, 115-130. Carbamate derivatives of hydroxy and aminogroups may also yield prodrugs. Carbonate derivatives, sulfonate esters,and sulfate esters of hydroxy groups may also provide prodrugs.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group may be an alkyl ester, optionallysubstituted with one or more ether, amine, or carboxylic acidfunctionalities, or where the acyl group is an amino acid ester asdescribed above, is also useful to yield prodrugs. Prodrugs of this typemay be prepared as described in Greenwald, et al., J Med Chem. 1996, 39,10, 1938-40. Free amines can also be derivatized as amides, sulfonamidesor phosphonamides. All of these prodrug moieties may incorporate groupsincluding ether, amine, and carboxylic acid functionalities.

The present invention also relates to pharmaceutically activemetabolites of the compounds of Formula (I), which may also be used inthe methods of the invention. A “pharmaceutically active metabolite”means a pharmacologically active product of metabolism in the body of acompound of Formula (I) or salt thereof. Prodrugs and active metabolitesof a compound may be determined using routine techniques known oravailable in the art. See, e.g., Bertolini, et al., J Med Chem. 1997,40, 2011-2016; Shan, et al., J Pharm Sci. 1997, 86 (7), 765-767;Bagshawe, Drug Dev Res. 1995, 34, 220-230; Bodor, Adv Drug Res. 1984,13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

The compounds of Formula (I) and their pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites of the present invention are useful as modulators of PHD inthe methods of the invention. “Modulators” include both inhibitors andactivators, where “inhibitors” refer to compounds that decrease,prevent, inactivate, desensitize or down-regulate PHD expression oractivity, and “activators” are compounds that increase, activate,facilitate, sensitize, or up-regulate PHD expression or activity.

The term “treat” or “treating” as used herein is intended to refer toadministration of an active agent or composition of the invention to asubject for the purpose of effecting a therapeutic or prophylacticbenefit through modulation of prolyl hydroxylase activity. Treatingincludes reversing, ameliorating, alleviating, inhibiting the progressof, lessening the severity of, or preventing a disease, disorder, orcondition, or one or more symptoms of such disease, disorder orcondition mediated through modulation of PHD activity. The term“subject” refers to a mammalian patient in need of such treatment, suchas a human.

Accordingly, the invention relates to methods of using the compoundsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition mediated by Prolyl Hydroxylase, such as:Anemia, vascular disorders, metabolic disorders, and wound healing.Symptoms or disease states are intended to be included within the scopeof “medical conditions, disorders, or diseases.”

As used herein the term “hypoxia” or “hypoxic disorder” refers to acondition where there is an insufficient level of oxygen provided in theblood or to tissues and organs. Hypoxic disorders can occur through avariety of mechanisms including where there is an insufficient capacityof the blood to carry oxygen (i.e. anemia), where there is an inadequateflow of blood to the tissue and/or organ caused by either heart failureor blockage of blood vessels and/or arteries (i.e. ischemia), wherethere is reduced barometric pressure (i.e. elevation sickness at highaltitudes), or where dysfunctional cells are unable to properly make useof oxygen (i.e. hystotoxic conditions). Accordingly, one of skill in theart would readily appreciate the present invention to be useful in thetreatment of a variety of hypoxic conditions including anemia, heartfailure, coronary artery disease, thromboembolism, stroke, angina andthe like.

In a preferred embodiment, molecules of the present invention are usefulin the treatment or prevention of anemia comprising treatment of anemicconditions associated with chronic kidney disease, polycystic kidneydisease, aplastic anemia, autoimmune hemolytic anemia, bone marrowtransplantation anemia, Churg-Strauss syndrome, Diamond Blackfan anemia,Fanconi's anemia, Felty syndrome, graft versus host disease,hematopoietic stem cell transplantation, hemolytic uremic syndrome,myelodysplastic syndrome, nocturnal paroxysmal hemoglobinuria,osteomyelofibrosis, pancytopenia, pure red-cell aplasia, purpuraSchoenlein-Henoch, refractory anemia with excess of blasts, rheumatoidarthritis, Shwachman syndrome, sickle cell disease, thalassemia major,thalassemia minor, thrombocytopenic purpura, anemic or non-anemicpatients undergoing surgery, anemia associated with or secondary totrauma, sideroblastic anemia, anemic secondary to other treatmentincluding: reverse transcriptase inhibitors to treat HIV, corticosteroidhormones, cyclic cisplatin or non-cisplatin-containingchemotherapeutics, vinca alkaloids, mitotic inhibitors, topoisomerase IIinhibitors, anthracyclines, alkylating agents, particularly anemiasecondary to inflammatory, aging and/or chronic diseases. PHD inhibitionmay also be used to treat symptoms of anemia including chronic fatigue,pallor and dizziness.

In another preferred embodiment, molecules of the present invention areuseful for the treatment or prevention of diseases of metabolicdisorders, including but not limited to diabetes and obesity. In anotherpreferred embodiment, molecules of the present invention are useful forthe treatment or prevention of vascular disorders. These include but arenot limited to hypoxic or wound healing related diseases requiringpro-angiogenic mediators for vasculogenesis, angiogenesis, andarteriogenesis

In treatment methods according to the invention, an effective amount ofa pharmaceutical agent according to the invention is administered to asubject suffering from or diagnosed as having such a disease, disorder,or condition. An “effective amount” means an amount or dose sufficientto generally bring about the desired therapeutic or prophylactic benefitin patients in need of such treatment for the designated disease,disorder, or condition. Effective amounts or doses of the compounds ofthe present invention may be ascertained by routine methods such asmodeling, dose escalation studies or clinical trials, and by taking intoconsideration routine factors, e.g., the mode or route of administrationor drug delivery, the pharmacokinetics of the compound, the severity andcourse of the disease, disorder, or condition, the subject's previous orongoing therapy, the subject's health status and response to drugs, andthe judgment of the treating physician. An example of a dose is in therange of from about 0.001 to about 200 mg of compound per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g.,BID, TID, QID). For a 70-kg human, an illustrative range for a suitabledosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about2.5 g/day.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the agents of the invention may be used in combination withadditional active ingredients in the treatment of the above conditions.The additional compounds may be co-administered separately with an agentof Formula (I) or included with such an agent as an additional activeingredient in a pharmaceutical composition according to the invention.In an exemplary embodiment, additional active ingredients are those thatare known or discovered to be effective in the treatment of conditions,disorders, or diseases mediated by PHD enzyme or that are active againstanother targets associated with the particular condition, disorder, ordisease, such as an alternate PHD modulator. The combination may serveto increase efficacy (e.g., by including in the combination a compoundpotentiating the potency or effectiveness of a compound according to theinvention), decrease one or more side effects, or decrease the requireddose of the compound according to the invention.

The compounds of the invention are used, alone or in combination withone or more other active ingredients, to formulate pharmaceuticalcompositions of the invention. A pharmaceutical composition of theinvention comprises: (a) an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, pharmaceutically acceptableprodrug, or pharmaceutically active metabolite thereof; and (b) apharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of a agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols. Suitable excipientsmay also include antioxidants. Such antioxidants may be used in apharmaceutical composition or in a storage medium to prolong theshelf-life of the drug product.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the compounds of the invention may be prepared usingsuitable pharmaceutical excipients and compounding techniques now orlater known or available to those skilled in the art. The compositionsmay be administered in the inventive methods by oral, parenteral,rectal, topical, or ocular routes, or by inhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration. A preferred mode of use of the invention is localadministration of PHD inhibitors particularly to sites where tissue hasbecome or has been made ischemic. This may be achieved via a specializedcatheter, angioplasty balloon or stent placement balloon.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. To prepare the oral compositions, the compounds may beformulated to yield a dosage of, e.g., from about 0.05 to about 100mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about0.1 to about 10 mg/kg daily.

Oral tablets may include a compound according to the invention mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservative agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquidoral excipients include ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, compounds of the invention may bemixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsulesmay be prepared by mixing the compound of the invention with water, anoil such as peanut oil or olive oil, liquid paraffin, a mixture of monoand di-glycerides of short chain fatty acids, polyethylene glycol 400,or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid compositions may optionally contain: pharmaceutically-acceptableexcipients such as suspending agents (for example, sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose,carboxymethylcellulose, aluminum stearate gel and the like); non-aqueousvehicles, e.g., oil (for example, almond oil or fractionated coconutoil), propylene glycol, ethyl alcohol, or water; preservatives (forexample, methyl or propyl p-hydroxybenzoate or sorbic acid); wettingagents such as lecithin; and, if desired, flavoring or coloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, the compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, thecompounds of the invention may be provided in sterile aqueous solutionsor suspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms will be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses may rangefrom about 1 to 1000 μg/kg/minute of compound, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery.

Compounds of the invention may alternatively be administered in methodsof this invention by inhalation, via the nasal or oral routes, e.g., ina spray formulation also containing a suitable carrier.

Abbreviations and acronyms used herein including the following:

Term Acronym Diisopropylethylamine DIEA Tetrahydrofuran THFDichloromethane DCM Dimethyl Sulfoxide DMSO 2-Methoxyethoxymethylchloride MEMCl or MEMchloride N,N-Dimethylformamide DMF Ethanol EtOHAcetonitrile ACN Ethyl Acetate EtOAc N-(3-Dimethylaminopropyl)-N- EDClethylcarbodiimide 1,8-Diazabicyclo[5.4.0]undec-7-ene DBU DichloroethaneDCE 1,2,3,4,5-Pentaphenyl-1′-(di-t- butylphosphino)ferrocene Q-Phose ®N-Chlorosuccinimide NCS N-Bromosuccinimide NBS

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I). Reactions may be performedbetween the melting point and the reflux temperature of the solvent, andpreferably between 0° C. and the reflux temperature of the solvent.Reactions may also be conducted in sealed pressure vessels above thenormal reflux temperature of the solvent.

Within each scheme provided herein, numbers for each formula arepresented for convenience only. Although generally specific to therespective scheme, these references however should not be consideredlimiting and each scheme, including all of its elements, are broadlyapplicable for various embodiments of the present invention.

Referring to Scheme A, protection of 2-chloro-1H-benzoimidazoles (II),is achieved using a suitable protecting group reagent such as2-methoxyethoxymethyl chloride (MEMCl) or 2-(trimethysilyl)-ethoxymethylchloride (SEMCl) in the presence of a base such as NaH or DIPEA in asolvent such as THF to provide compounds of formula (III). Displacementof the 2-chloro substituent with commercially availablepyrazole-4-carboxylates of formula (IV), where R² and R³ are both H, CF₃or CH₃, is accomplished in a polar aprotic solvent such as DMF,N,N-dimethylacetamide (DMA), or THF, or a mixture thereof, in thepresence of a suitable base such as Cs₂CO₃, K₂CO₃, Na₂CO₃, NaH, or amixture thereof at elevated temperatures generally ranging between 80°C. and 120° C. Subsequent deprotection of PG using an acid such as HClin an appropriate solvent such as EtOH provides intermediates of formula(VIII). Saponification with a suitable base such as aq. NaOH, aq. LiOHor aq. KOH or a mixture thereof in a solvent such as THF providescompounds of Formula (I).

Aryl ether and aryl thioether intermediates of formula (VIII) areprepared according to Scheme B, where each R¹ can be H, —Cl, —F, —CF₃,or —OCF₃ provided that at least one R¹ is —Cl or —F. Commerciallyavailable substituted halo-nitro-phenylamines (VII) are reacted withsubstituted phenols, thiophenols, and substituted phenyl-alkylthiols inthe presence of a base such as K₂CO₃, in a solvent such as DMF and thelike, at temperatures between room temperature and the refluxtemperature of the solvent, to provide nitro intermediates of formula(VIII), where R^(e) is an aryl, —C₁₋₄alkyl-aryl, or heteroaryl ring.Alkyl ether and thioalkyl ether intermediates of formula (VIII), whereR^(e) is a C₁₋₆alkyl (branched or straight chain), are prepared by thereaction of optionally substituted halo-nitro-phenylamines with alcoholsand alkylthiols in the presence of a base such as sodium methoxide,sodium-tert-butoxide, and the like, in a solvent such as MeOH, attemperatures ranging from room temperature to the reflux temperature ofthe solvent. Reactions may also be performed in a sealed tube attemperatures above the reflux temperature of the solvent. Thioalkylintermediates of formula (VIII), are also synthesized by the reaction ofoptionally substituted halo-nitro phenylamines of formula (VII) withsodium thiomethoxide, sodium thioethoxide, sodium thioisopropoxide andthe like, in a solvent such as DMF, at temperatures ranging from 80° C.to 100° C.

Amino intermediates of formula (X) are prepared according to Scheme B,where R¹ is H, —Cl, —F, —CF₃, or —OCF₃. Substitutedhalo-nitro-phenylamines (IX) and cycloalkyl and heterocycloalkyl aminesare heated in a sealed tube at temperatures ranging from 80° C. to 100°C., to provide nitro intermediates of formula (X).

2-Nitro-phenyl amines (XIV) are prepared according to Scheme C. Anilinesof general formula (XI), where one or more R¹s are H, —Cl, —CN, —F and—CF₃, are reacted with acetic anhydride in a solvent such as toluene, inthe presence of a base such as DMAP, at temperatures ranging from roomtemperature to the boiling point of the solvent, to afford acetylatedintermediates of formula (XII). Subsequent nitration is achieved byreacting intermediates of formula (XII) with a nitrating reagent such asKNO₃ and an acid such as sulfuric acid, at 0° C., to afford nitratedintermediates of formula (XIII). Subsequent deprotection of the acetylgroup with aqueous acid such as hydrochloric acid under heating affordsnitro anilines of the formula (XIV).

According to Scheme D, 2-halo-nitro anilines of formula (XVI) areprepared by the reaction of nitro anilines of formula (XV) with achlorinating or brominating reagent such as NCS or NBS, at temperaturesranging from 80° C. to 120° C., in a solvent such as DMF. Additionally,halo-nitro benzene intermediates of formula (XVII), where R¹ isindependently —F and —Br, are reacted with 7M ammonia in MeOH and heatedconventionally or in a sealed tube at temperatures ranging from 50° C.to 70° C. to provide halo-nitro anilines of formula (XVIII).

2-Chloro-1H-benzoimidazole intermediates of formula (XXV) are preparedby three methods as shown in Scheme E. Substituted nitro-phenylamines(either commercially available nitrophenylamines, knownnitrophenylamines or nitrophenylamines prepared using the schemes asprovided) are reduced by employing reduction methods known to oneskilled in the art, such as zinc powder in the presence of a saturatedaqueous solution of NH₄Cl in a solvent such as acetone, and the like, attemperatures ranging from 0° C. to room temperature, to provide diamineintermediates of formula (XX). Reaction of diamine intermediates offormula (XX), either commercially available or synthetically accessiblediamines, with carbonyl diimidazole, in a solvent such as THF and thelike, at temperatures between 0° C. and room temperature, provides1,3-dihydro-benzoimidazol-2-one intermediates of formula (XXI).Subsequent chlorination of (XXI) using methods known to one skilled inthe art, for example, employing neat phosphorus oxychloride (POCl₃),with heating, gives 2-chloro-1H-benzoimidazoles of formula (XXII).Subsequent protection of 1H-benzoimidazoles (XXII) is achieved using asuitable protecting group reagent such as dimethylsulfamoyl chloride,2-methoxyethoxymethyl chloride (MEMCl) or 2-(trimethysilyl)-ethoxymethylchloride (SEMCl), in the presence of a suitable base in a solvent suchas THF or DMF to provide compounds of formula (XXV).

Additionally, benzoimidazoles of formula (XXIII) are prepared in one-potsynthesis from o-nitroanilines via a reductive cyclization in thepresence of a suitable reducing agent such as SnCl₂.H₂O, sodiumdithionate, and the like, in the presence of an aldehyde or aldehydeequivalent such as trimethyl orthoformate, and the like, or an acidsource such as acetic acid, formic acid, and the like, underconventional heating, heating in a sealed tube or microwave heating attemperatures ranging from 80° C. to 130° C. In addition to the one potreductive cyclization reaction described above, 1H-benzoimidazoles offormula (XXIII) are also synthesized by the reaction of diamines offormula (XX) in the presence of an aldehyde or aldehyde equivalent suchas trimethyl orthoformate, and an acid such as HCl at temperaturesranging from 0° C. to room temperature. Subsequent protection of1H-benzoimidazoles (XXIII) is achieved using a suitable protecting groupreagent such as 2-methoxyethoxymethyl chloride (MEMCl) or2-(trimethysilyl)-ethoxymethyl chloride (SEMCl) in the presence of abase such as NaH or DIPEA in a solvent such as THF to provide compoundsof formula (XXIV). Deprotonation of the protected 1H-benzoimidazoleintermediate (XXIV) with an organolithium base such as butyllithuim orlithium diisopropylamide, in a solvent such as THF, at temperaturesranging from ⁻80° C. to ⁻40° C., followed by the addition ofN-chlorosuccinimide and the like, affords 2-chloro-1H-benzoimidazoleintermediates of formula (XXV).

Referring to Scheme F, compounds of formula (III) where W is—CO₂C₁₋₄alkyl and R¹ is H, —F, —Cl, —CF₃ or —OCF₃, are saponified with asuitable base such as aq. NaOH, aq. LiOH or aq. KOH or a mixturethereof, at temperatures ranging from room temperature to the boilingpoint of the solvent, in a solvent such as THF, provides compounds offormula (XXVI). Subsequent amide bond formation employing methods knownto one skilled in the art, provides benzoimidazole intermediates offormula (XXVII). Alternatively, benzoimidazole intermediates of formula(III), where W is —CO₂Me, are reduced with a suitable reducing agentsuch as lithium aluminum hydride, in a solvent such as THF, at 0° C., toafford the corresponding alcohol intermediate of formula (XXVIII).Alkylation of intermediate (XXVIII), employing a base such as NaH,alkylating agents such as alkyl halides and aryl halides, in a solventsuch as DMF, provides benzoimidazole intermediates of formula (XXIX).

Referring to Scheme G, benzoimidazole intermediates of formula (XXX)under Suzuki conditions, where W is a suitable halogen or triflate andeach R¹ is independently H, —Cl, —F, —CF₃ or —OCF₃, are reacted witharyl boronic acids or esters, in the presence of an organotransitionmetal catalyst such as PdCl₂(dppf) and a suitable base such as CsF toprovide biaryl intermediates of formula (XXXI), where Y is a substitutedor unsubstituted aryl or heteroaryl ring.

Referring to Scheme G, benzoimidazole intermediates of formula (XXX),where W is —S—C₁₋₄alkyl or —S—Ar (where Ar is a suitably substitutedphenyl group), and each R¹ is independently H, —F, —Cl, —CF₃ or —OCF₃,are oxidized employing methods known to one skilled in the art, forexample, employing an oxidizing agent such as potassiumperoxomonosulfate, 3-chloroperoxybenzoic acid, and the like, to providethe corresponding sulfone and sulfoxide intermediates of formula (XXXI),where Y is —S(O)—C₁₋₄alkyl, —S(O)₂—C₁₋₄alkyl, —S(O)-aryl, or—S(O)₂-aryl.

Referring to Scheme G, benzoimidazole intermediates of formula (XXX),where W is —NO₂, and each R¹ is independently H, —Cl, —F, —CF₃ or —OCF₃,are reacted with a reducing agent, employing methods known to oneskilled in the art, to provide benzoimidazole intermediates of formula(XXXI), where Y is —NH₂, and R¹ is —Cl, —CF₃ or —OCF₃.

Referring to Scheme G, benzoimidazole intermediates of formula (XXX),where W is —NH₂, and each R¹ is independently H, —Cl, —F, —CF₃ or —OCF₃,under reductive amination conditions employing methods known to oneskilled in the art, are reacted with alkyl aldehydes and substitutedaryl aldehydes, to provide alkyl and benzyl substituted aminointermediates of formula (XXXI), where Y is —NH—C₁₋₄alkyl or—NH—CH₂-aryl.

Referring to Scheme G, benzoimidazole intermediates of formula (XXX),where W is —NH₂, and each R¹ is independently H, —Cl, —F, —CF₃ or —OCF₃,are reacted with alkyl, aryl and cycloalkylsulfonyl chlorides, acyl andaryl chlorides, 2-bromoacetyl bromides and the like, to provide thecorresponding substituted sulfonamide and amide intermediates.

Referring to Scheme G, benzoimidazole intermediates of formula (XXX),where W is —NH₂, and each R¹ is independently H, —Cl, —F, —CF₃ or —OCF₃,are reacted under amination conditions with an aryl bromide, anorganotransition metal catalyst such as Pd(dba)₂, a ligand such asQ-Phos, a suitable base such as sodium tert-butoxide, in a solvent suchas toluene, at temperatures ranging from room temperature to the boilingpoint of the solvent, to provide intermediates of formula (XXXI) where Yis —NHAr.

Referring to Scheme G, benzoimidazole intermediates of formula (XXX),where W is —NC(O)CH₂Br, and each R¹ is independently H, —Cl, —F, —CF₃ or—OCF₃, are reacted with heterocycloalkylamines, such as morpholine,N-methylpiperazine, piperidine, and the like, in a solvent such asdichloromethane, at temperatures ranging from 0° C. to room temperature,to provide substituted acetyl amino benzoimidazole intermediates.

Referring to Scheme G, benzoimidazole intermediates of formula (XXX),where W is —S-^(t)Bu and each R¹ is independently H, —F, —Cl, —CF₃ or—OCF₃, are treated with 2-nitro benzene sulfenyl chloride in thepresence of a base such as K₂CO₃ to provide the disulfide intermediate.Subsequent reduction of the disulfide with a reducing agent such asNaBH₄, in aqueous EtOH, at 0° C. affords the thiol intermediate (incertain circumstances, the thiol intermediate may dimerize upon itselfto provide a disulfide by-product). Alkylation of the thiol with benzyland alkyl bromides in the presence of base such as K₂CO₃, affordsthioalkylated benzoimidazole intermediates of formula (XXXI), where Y is—S—C₁₋₄alkyl or —S—C₁₋₄alkyl-aryl. Additionally, the disulfideby-product as described above is reacted with NCS and aqueous HCl, in asolvent such as acetonitrile, at 0° C., to afford chlorosulfonylintermediates (A. Nishiguchi, K. Maeda, S. Miki. Synthesis, 2006, 24,4131-4134) which upon reaction with an appropriate aniline, in a solventsuch as pyridine, provides aryl-sulfamoyl intermediates of formula(XXXI), where Y is —SO₂—NH-aryl.

Deprotection of intermediates-PG (XXXI) using an acid such as HCl in anappropriate solvent such as EtOH followed by saponification of thecarboxy group on the pyrazole ring using a suitable base such as aq.NaOH, aq. LiOH or aq. KOH or a mixture thereof in a solvent such as THF,at temperatures between room temperature and the reflux temperature ofthe solvent provides compounds of Formula (I).

Additionally, conversion of intermediates of formula (XXXI) to compoundsof Formula (I) is achieved in one step with acetic acid and aqueoushydrochloric acid at temperatures ranging from 80° C. to 100° C.

Benzoimidazoles of the formula (VI) can also be prepared according toScheme H. Bromoanilines of general formula (XXXII) are treated withbenzoyl isothiocyanate in a solvent such as toluene, in the presence ofa base such as DMAP, at room temperature, to afford the correspondingthiourea derivative of formula (XXXIII). The benzoyl group is removedusing a base such as sodium methoxide, in a solvent such as MeOH, at 0°C., to afford the thiourea derivative of formula (XXXIV). Reaction ofthioureas of formula (XXXIV) with lead (II) acetate trihydrate in thepresence of a base such as potassium hydroxide, in a solvent such aswater, at temperatures ranging from 80° C. to 100° C., providescyanamide intermediates of formula (XXXV). Subsequent reaction of thecyanamide intermediate with 1H-pyrazole-4-carboxylic acid ethyl ester,in the presence of an anhydrous acid such as HCl, in a solvent such asdioxane, at elevated temperatures such as 80° C. to 100° C., providesguanidine intermediates of formula (XXXVI). Further treatment of theguanidine intermediate with a coupling reagent such as CuI, and a basesuch as Cs₂CO₃, in a solvent such as DMF, at temperatures of 60° C. to100° C., provides benzoimidazole intermediates of the formula (VI).

Benzoimidazole intermediates of formula (XXXIX) are synthesizedaccording to Scheme I. Commercially available 1H-pyrazole-4-carboxylicacid ethyl ester (IV), is reacted with cyanamide, in a solvent such asdioxane, in the presence of an acid such as 4M HCl in dioxane, attemperatures ranging from 80° C. to 100° C., to providecarbamimidoyl-pyrazole-4-carboxylic acid ethyl esters of formula(XXXVII). Subsequent reaction of carbamimidoyl-pyrazole-4-carboxylicacid ethyl esters (XXXVII) with commercially available2,3-dihalo-aromatic intermediates of formula (XXXVIII), where Z is oneor two N (for example 2,3-dichloro-quinoxaline), and a base such asCs₂CO₃ (catalysts such as CuI and the like, may optionally be employed)in a solvent such as DMF, DMA and the like, at temperatures ranging fromroom temperature to the boiling point of the solvent, providesbenzoimidazole intermediates of formula (XXXIX).

Compounds of Formula (I) may be converted to their corresponding saltsusing methods known to those skilled in the art. For example, acids ofFormula (I) may be treated with K₂CO₃ in water, in a solvent such asEtOH, at temperatures ranging from room temperature to the refluxtemperature of the solvent, to provide the corresponding salt forms.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, byenantio-, diastero-, or regiospecific synthesis, or by resolution.Compounds prepared according to the schemes above may alternately beobtained as racemic (1:1) or non-racemic (not 1:1) mixtures or asmixtures of diastereomers or regioisomers. Where racemic and non-racemicmixtures of enantiomers are obtained, single enantiomers may be isolatedusing conventional separation methods known to one skilled in the art,such as chiral chromatography, recrystallization, diastereomeric saltformation, derivatization into diastereomeric adducts,biotransformation, or enzymatic transformation. Where regioisomeric ordiastereomeric mixtures are obtained, single isomers may be separatedusing conventional methods such as chromatography or crystallization.

For starting materials requiring stereospecific amino acid chemistry,these materials were purchased as preferred stereospecific enantiomerswhich retained their specificity throughout the synthesis reactions.

The following examples are provided to further illustrate the inventionand various preferred embodiments.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, byenantio-, diastero-, or regiospecific synthesis, or by resolution.Compounds prepared according to the schemes above may alternately beobtained as racemic (1:1) or non-racemic (not 1:1) mixtures or asmixtures of diastereomers or regioisomers. Where racemic and non-racemicmixtures of enantiomers are obtained, single enantiomers may be isolatedusing conventional separation methods known to one skilled in the art,such as chiral chromatography, recrystallization, diastereomeric saltformation, derivatization into diastereomeric adducts,biotransformation, or enzymatic transformation. Where regioisomeric ordiastereomeric mixtures are obtained, single isomers may be separatedusing conventional methods such as chromatography or crystallization.

For starting materials requiring stereospecific amino acid chemistry,these materials were purchased as preferred stereospecific enantiomerswhich retained their specificity throughout the synthesis reactions.

The following examples are provided to further illustrate the inventionand various preferred embodiments.

EXAMPLES Chemistry:

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt). Where solutions were “dried,” they were generallydried over a drying agent such as Na₂SO₄ or MgSO₄. Where mixtures,solutions, and extracts were “concentrated”, they were typicallyconcentrated on a rotary evaporator under reduced pressure.

Thin-layer chromatography (TLC) was performed using Merck silica gel 60F₂₅₄ 2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gelplates. Preparative thin-layer chromatography was performed using EMScience silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates with a20 cm×4 cm concentrating zone.

Normal-phase flash column chromatography (FCC) was performed on silicagel (SiO₂) eluting with 2 M NH₃ in MeOH/DCM, unless otherwise noted.Reversed-phase HPLC was performed on a Hewlett Packard HPLC Series 1100,with a Phenomenex Luna C18 (5 μm, 4.6×150 mm) column. Detection was doneat λ=230, 254 and 280 nm. The gradient was 10 to 99% acetonitrile/water(0.05% trifluoroacetic acid) over 5.0 min with a flow rate of 1 mL/min.Alternatively, HPLC was performed on a Dionex APS2000 LC/MS with aPhenomenex Gemini C18 (5 μm, 30×100 mm) column, and a gradient of 5 to100% acetonitrile/water (20 mM NH₄OH) over 16.3 min, and a flow rate of30 mL/min.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD equippedwith a ESI/APCI positive and negative multimode source unless otherwiseindicated.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. The format of the ¹H NMR data below is: chemicalshift in ppm downfield of the tetramethylsilane reference (apparentmultiplicity, coupling constant J in Hz, integration). Chemical nameswere generated using ChemDraw Version 6.0.2 (CambridgeSoft, Cambridge,Mass.) or ACD/Name Version 9 (Advanced Chemistry Development, Toronto,Ontario, Canada).

Example 1: 1-(1H-Benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

Step A: Preparation of2-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.According to Scheme A, a mixture of NaH (60% dispersion in oil, 0.40 g,9.8 mmol) and THF (10 mL) was cooled to 0° C., then solid2-chlorobenzoimidazole (1.0 g, 6.5 mmol) was added portion wise over 10min. The resulting mixture was stirred at 0° C. for 1 h, then2-(trimethylsilyl)-ethoxymethyl chloride (1.5 mL, 8.5 mmol) was added.The reaction mixture was allowed to warm to 23° C. and was stirred 16 h.The mixture was carefully poured over ice (200 g) and then was extractedwith Et₂O (3×100 mL). The combined organic extracts were dried,filtered, and concentrated. The residue was purified (FCC) (1:99 to15:85 EtOAc/hexanes) to yield the titled compound, which has beenpreviously described (WO 2005/012296, Janssen Pharmaceutica N.V.,Example 7).

Step B:1-[1-(2-Trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. A mixture of2-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (0.34 g,1.2 mmol), ethyl pryazole-4-carboxylate (0.24 g, 1.7 mmol), cesiumcarbonate (0.78 g, 2.4 mmol), and anhydrous DMF (2.5 mL) was stirred at100° C. for 5 h. The mixture was allowed to cool to 23° C. and wasdiluted with EtOAc, then filtered through a pad of silica gel. Theresulting solution was concentrated. The residue was purified (FCC)(5:95 to 40:60 EtOAc/hexanes) to yield the titled compound (0.36 g,77%). ¹H NMR (500 MHz, CDCl₃): 8.88 (s, 1H), 8.18 (s, 1H), 7.77-7.69 (m,1H), 7.60-7.50 (m, 1H), 7.40-7.30 (m, 2H), 6.03 (s, 2H), 4.34 (q, J=7.1Hz, 2H), 3.57-3.50 (m, 2H), 1.37 (t, J=7.1, Hz, 3H), 0.87-0.80 (m, 2H),−0.11 (s, 9H).

Step C: 1-(1H-Benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethylester hydrochloride. A solution of HCl and dioxane (4M, 2 mL, 8 mmol)was added to a mixture of1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrrole-3-carboxylicacid ethyl ester (0.30 g, 0.78 mmol) and EtOH (4 mL). The reactionmixture was heated to reflux for 30 min, then cooled to 23° C. Et₂O wasadded (20 mL), and the mixture was cooled to 0° C. for 10 min. Theresulting precipitate was collected by filtration and washed well withEt₂O to afford the titled compound (0.18 g, 91%). MS (ESI/CI): masscalcd. for C₁₃H₁₂N₄O₂, 256.3; m/z found, 257.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 8.96 (s, 1H), 8.33 (s, 1H), 7.56 (s, 2H), 7.28-7.21 (m, 2H),4.30 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H)

Step D: 1-(1H-Benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. Asolution of LiOH and H₂O (1.0 M, 1.0 mL, 1.0 mmol) was added to amixture of 1-(1H-benzoimidazol-2-yl)-1H-pyrrole-3-carboxylic acid ethylester hydrochloride (0.040 g, 0.16 mmol) and THF (2.0 mL), and thereaction mixture was stirred at 23° C. for 16 h. The THF was removed invacuo and then aqueous HCl (1.0 M, 2 mL, 2 mmol) was added at 0° C. Theresulting precipitate was collected and washed with water to give thetitled compound (0.033 g, 90%). MS (ESI/CI): mass calcd. for C₁₁H₈N₄O₂,228.2; m/z found, 229.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 13.32 (s,1H), 13.00-12.86 (br s, 1H), 8.90 (d, J=0.6 Hz, 1H), 8.28 (d, J=0.6 Hz,1H), 7.64 (d, J=4.6 Hz, 1H), 7.49 (d, J=5.5 Hz, 1H), 7.28-7.20 (m, 2H).

Example 2:1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

Method A:

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 2,5,6-trichloro-1H-benzoimidazole for2-chlorobenzoimidazole in Step A. MS (ESI/CI): mass calcd. forC₁₁H₆Cl₂N₄O₂, 297.1; m/z found, 296.0 [M−H]⁻. ¹H NMR (500 MHz, DMSO-d₆):14.18-12.52 (br s, 2H), 8.89 (d, J=0.5 Hz, 1H), 8.31 (d, J=0.5 Hz, 1H),7.80 (s, 2H).

Method B:

Step A: 5,6-Dichloro-1,3-dihydro-benzoimidazol-2-one: To the solution of4,5-dichloro-benzene-1,2-diamine (25 g, 0.14 mol) in dry DMF (200 mL),was added CDI (23 g, 0.14 mol) as the solid. The reaction solution wasstirred at room temperature for 1 hour, then water (500 mL) was added.The precipitated solid was collected by filtration, washed with water,dried thoroughly to afford the titled compound (26.0 g, 90%). The crudeproduct was used in the following reaction without further purification.

Step B: 2,5,6-Trichloro-1H-benzoimidazole: Thoroughly dried5,6-dichloro-1,3-dihydro-benzoimidazol-2-one (28.4 g, 0.14 mol) wassuspended in POCl₃ (75 mL). The reaction solution was heated to refluxtemperature for 3 hours and cooled to room temperature. The solution waspoured into crushed ice/water (1.5 L) slowly with sufficient stirring.The solution was neutralized to pH=7.0 with NaOH. The precipitated solidwas collected by filtration, washed with water, and dried to afford thetitle compound (27.9 g, 90%). The crude product was used in thefollowing reaction without further purification.

Step C:1-(5,6-Dichloro-1-dimethylsulfamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester. 2,5,6-Trichloro-1H-benzoimidazole 2 (27.6 g, 0.125mol) was dissolved in dry DMF (200 mL) and then K₂CO₃ (20.7 g, 0.15 mol)and dimethylsulfamoyl chloride (17.9 g, 0.125 mol) were added. Thereaction mixture was stirred at room temperature for 16 hours. HPLCanalysis showed the complete formation of2,5,6-trichloro-benzoimidazole-1-sulfonic acid dimethylamide. In thesame pot, without isolation of 2,5,6-trichloro-benzoimidazole-1-sulfonicacid dimethylamide, was added 1H-pyrazole-4-carboxylic acid ethyl ester(17.5 g, 0.125 mol) and K₂CO₃ (20.7 g, 0.15 mol). The reaction mixturewas stirred at 70° C. for 4 hours and water (500 mL) was added while thereaction solution was still hot. The reaction solution was cooled toroom temperature. The precipitated solid was collected via filtration,washed with water and dried. The crude product was used in the followingreaction without further purification.

Step D: 1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. Crude1-(5,6-Dichloro-1-dimethylsulfamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester was dissolved in THF (125 mL) and LiOH.H₂O (21 g, 0.5mol) in water (250 mL) was added. The reaction mixture was stirred atreflux temperature for 2 hours and cooled to room temperate.Concentrated HCl was added to adjust pH to 2.0. The solid precipitatedwas collected by filtration, washed with water and dried. The solid wastriturated in hot EtOAc (1 L). After cooling to room temperature andfiltration, the pure compound was obtained as a tan solid (18.5 g, 50%).MS [M+H]⁺ found 297.0. ¹H NMR (500 MHz, DMSO-d₆): 13.71 (s, 1H), 12.99(s, 1H), 8.90 (s, 1H), 8.32 (s, 1H), 7.94 (s, 1H), 7.67 (s, 1H). Thepotassium salt of1-(5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid wasprepared by suspending the free acid (55 g, 1.7 mol) in EtOH (1.5 L) atreflux temperature and then K₂CO₃ (12.79 g, 0.85 mol) in 20 mL water wasadded dropwise over 5 min. Strong mechanic stirring was required toensure proper agitation. The suspension was stirred at refluxtemperature for 8 hours and then cooled to room temperature over 5hours. The precipitated solid was collected by filtration and washedwith water (100 mL) quickly and then EtOH. The potassium salt wasobtained as a white solid (38 g, 65%). The mother liquor wasconcentrated and the above process was repeated once to give the secondcrop of the potassium salt (13 g, 22%). MS [M+H]⁺=297.0. ¹H NMR (500MHz, DMSO-d₆): 8.65 (s, 1H), 7.96 (s, 1H), 7.57 (s, 2H).

Example 3:1-(5-Trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 2-chloro-5-trifluoromethyl-1H-benzoimidazole for2-chlorobenzoimidazole in Step A. MS (ESI/CI): mass calcd. forC₁₂H₇F₃N₄O₂, 296.2; m/z found, 295.0 [M−H]⁻. ¹H NMR (500 MHz, DMSO-d₆):14.44-12.32 (br s, 2H), 8.94 (d, J=0.5 Hz, 1H), 8.33 (d, J=0.5 Hz, 1H),7.96-7.83 (br. s, 1H), 7.75 (br d, 1H), 7.58 (dd, J=8.49, 1.41 Hz, 1H).

Example 4:1-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 2,5-dichloro-6-fluoro-1H-benzoimidazole for2-chlorobenzoimidazole in Step A. MS (ESI/CI): mass calcd. forC₁₁H₆ClFN₄O₂, 280.7; m/z found, 279.0 [M−H]⁻. ¹H NMR (500 MHz, DMSO-d₆):14.21-12.25 (br s, 2H), 8.88 (d, J=0.6 Hz, 1H), 8.30 (d, J=0.6 Hz, 1H),7.81-7.67 (br s, 1H), 7.65-7.52 (br s, 1H).

Example 5:1-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 2-chloro-5,6-dimethyl-1H-benzoimidazole for2-chlorobenzoimidazole in Step A. MS (ESI/CI): mass calcd. forC₁₃H₁₂N₄O₂, 256.3; m/z found, 257.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):13.16-12.81 (m, 2H), 8.85 (d, J=0.6 Hz, 1H), 8.25 (d, J=0.6 Hz, 1H),7.43-7.21 (br s, 2H), 2.31 (s, 6H).

Example 6: 1-(5-Bromo-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 5-bromo-2-chloro-1H-benzoimidazole for2-chlorobenzoimidazole in Step A. MS (ESI/CI): mass calcd. forC₁₁H₇BrN₄O₂, 306.0; m/z found, 307.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):8.82 (d, J=0.5 Hz, 1H), 8.22 (s, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.45 (d,J=8.5 Hz, 1H), 7.32 (dd, J=8.5, 1.9 Hz, 1H).

Example 7: 1-(5-Methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 2-chloro-5-methoxy-1H-benzoimidazole for2-chlorobenzoimidazole in Step A. MS (ESI/CI): mass calcd. forC₁₂H₁₀N₄O₃, 258.2; m/z found, 259.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆,tautomeric mixture): 13.16 (s, 1H), 12.91 (s, 1H), 8.84 (s, 1H), 8.26(s, 1H), 6.83-7.54 (m, 3H), 3.80 (s, 3H).

Example 8:1-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 2,4-dichloro-6-trifluoromethyl-1H-benzoimidazole for2-chlorobenzoimidazole in Step A. MS (ESI/CI): mass calcd. forC₁₂H₆ClF₃N₄O₂, 330.7; m/z found, 329.0 [M−H]⁻. ¹H NMR (500 MHz,DMSO-d₆): 13.90-14.50 (br s, 1H), 12.75-13.45 (br s, 1H), 8.95 (s, 1H),8.36 (s, 1H), 7.72 (s, 1H), 7.70 (s, 1H).

Example 9:1-(5,6-Dimethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 2-chloro-5,6-dimethoxy-1H-benzoimidazole for2-chlorobenzoimidazole in Step A. MS (ESI/CI): mass calcd. forC₁₃H₁₂N₄O₄, 288.3; m/z found, 289.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):8.81 (s, 1H), 8.25 (s, 1H), 7.09 (s, 2H), 3.80 (s, 6H).

Example 10:1-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 2-chloro-4,5-dimethyl-1H-benzoimidazole for2-chlorobenzoimidazole in Step A. MS (ESI/CI): mass calcd. forC₁₃H₁₂N₄O₂, 256.3; m/z found, 257.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆,tautomeric mixture): 12.60-13.30 (br. m, 2H), 8.83-8.90 (m, 1H),8.23-8.29 (m, 1H), 7.0-7.35 (m, 2H), 2.47 (s, 3H), 2.33 (s, 3H).

Example 11:1-(5-Trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 2-chloro-5-trifluoromethoxy-1H-benzoimidazole for2-chlorobenzoimidazole in Step A. MS (ESI/CI): Mass calcd. forC₁₂H₇F₃N₄O₃ 312.0. m/z found: 313.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):8.91 (s, 1H), 8.31 (s, 1H), 7.83-7.41 (m, 2H), 7.30-7.21 (m, 1H).

Example 12:1-{5-[3-(3-Chloro-benzyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylicacid

Step A:1-{5-[3-(3-Chloro-benzyloxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylicacid ethyl ester and1-{6-[3-(3-Chloro-benzyloxy)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylicacid ethyl ester. According to Scheme B,[1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium (0.12 g, 0.16mmol) was added to a mixture of cesium fluoride (0.33 g 2.2 mmol),3-(3′-chlorobenzyloxy)phenylboronic acid (0.37 g, 1.3 mmol),1-[5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester and1-[6-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 6). MS (ESI/CI): Mass calcd.for C₁₉H₂₅BrN₄O₃Si, 464.1; m/z found, 465.1), (0.5 g, 1.1 mmol), and DME(5 ml) in a sealable tube. The reaction was stirred at 80° C. After 3 h,the mixture was cooled to rt, then was diluted with EtOAc (50 ml) andfiltered. The filtrate was concentrated. The residue was purified (FCC)(15:85 EtOAc/hexanes) to yield the titled compounds as a regioisomericmixture (0.47 g, 72%). MS (ESI/CI): mass calcd. for C₃₂H₃₅ClN₄O₄Si,602.2; m/z found, 603.2 [M+H]⁺.

Step B:1-{5-[3-(3-Chloro-benzyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to Example1, Steps C-D. MS (ESI/CI): mass calcd. for C₂₄H₁₇ClN₄O₃ 444.1; m/zfound, 445.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.93 (d, J=0.5 Hz, 1H),8.32 (s, 1H), 7.84-7.79 (m, 1H), 7.68-7.63 (m, 1H), 7.60-7.55 (m, 2H),7.52-7.37 (m, 4H), 7.36-7.27 (m, 2H), 7.03 (dd, J=7.8, 2.1 Hz, 1H), 5.26(s, 2H).

Example 13:1-{5-[3-(2-Chloro-benzyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 12,substituting 3-(2′-chlorobenzyloxy)phenylboronic acid for3-(3′-chlorobenzyloxy)phenylboronic acid in Step A. MS (ESI/CI): masscalcd. for C₂₄H₁₇ClN₄O₃, 444.1; m/z found, 445.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): 8.91 (s, 1H), 8.30 (s, 1H), 7.80 (s, 1H), 7.72-7.60 (m,2H), 7.59-7.48 (m, 2H), 7.48-7.36 (m, 3H), 7.36-7.25 (m, 2H), 7.02 (dd,J=8.1, 1.9 Hz, 1H), 5.27 (s, 2H).

Example 14:1-{5-[3-(4-Chloro-benzyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 12,substituting 3-(4′-chlorobenzyloxy)phenylboronic acid for3-(3′-chlorobenzyloxy)phenylboronic acid in Step A. MS (ESI/CI): masscalcd. for C₂₄H₁₇ClN₄O₃, 444.1; m/z found, 445.1 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 8.91 (s, 1H), 8.30 (s, 1H), 7.98-7.50 (m, 5H), 7.50-7.44(m, 2H), 7.43-7.35 (m, 1H), 7.35-7.22 (m, 2H), 7.00 (s, 1H), 5.22 (s,2H).

Example 15:1-[5-(3-Benzyloxy-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 12,substituting 3-(benzyloxy)phenylboronic acid for3-(3′-chlorobenzyloxy)phenylboronic acid in Step A. MS (ESI/CI): masscalcd. for C₂₄H₁₈N₄O₃, 410.1; m/z found, 411.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 8.99 (s, 1H), 8.38 (s, 1H), 8.02-7.28 (m, 11H), 7.09 (dd,J=8.1, 1.9 Hz, 1H), 5.31 (s, 2H).

Example 16:1-[5-(4-Benzyloxy-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 12,substituting 4-(benzyloxy)phenylboronic acid for3-(3′-chlorobenzyloxy)phenylboronic acid in Step A. MS (ESI/CI): masscalcd. for C₂₄H₁₈N₄O₃, 410.1; m/z found; 411.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 9.00 (s, 1H), 8.39 (s, 1H), 7.81-7.39 (m, 10H), 7.20 (d, J=8.8Hz, 2H), 5.26 (s, 2H).

Example 17:1-[5-(3-Trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 12,substituting 3-trifluoromethylphenyl boronic acid for3-(3′-chlorobenzyloxy)phenylboronic acid in Step A. MS (ESI/CI): masscalcd. for C₁₈H₁₁F3N₄O₂, 372.1; m/z found, 373.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): 8.91 (s, 1H), 8.31 (s, 1H), 8.11-7.79 (m, 3H), 7.78-7.52(m, 4H).

Example 18:1-[5-(3,4-Dichloro-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 12,substituting 3,4-dichlorophenylboronic acid for3-(3′-chlorobenzyloxy)phenylboronic acid in Step A. MS (ESI/CI): Masscalcd. for C₁₇H₁₀Cl₂N₄O₂ 372.0. m/z found: 373.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): 9.01 (s, 1H), 8.41 (s, 1H), 8.06 (s, 1H), 7.95 (s, 1H),7.81 (d, J=1.2 Hz, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.69 (dd, J=8.5, 1.7 Hz,1H).

Example 19:1-(5-Bromo-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 5-bromo-2-chloro-1H-benzoimidazole for2-chlorobenzoimidazole in Step A and3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester ethylpryazole-4-carboxylate in step B. MS (ESI/CI): mass calcd. forC₁₂H₆BrF₃N₄O₂, 374.0; m/z found, 375.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 13.69 (brs, 1H), 9.09 (s, 1H), 7.79 (br s, 1H), 7.55 (br s,1H), 7.43 (dd, J=8.4, 1.6 Hz, 1H).

Example 20:1-(5,6-dichloro-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 2,5,6-trichloro-1H-benzoimidazole for2-chlorobenzoimidazole in Step A and3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester ethylpryazole-4-carboxylate in step B. MS (ESI/CI): mass calcd. forC₁₂H₅Cl₂F₃N₄O₂, 365.1; m/z found, 363.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 13.25-14.30 (brs, 2H), 9.10 (s, 1H), 7.87 (br s, 2H).

Example 21:1-(5-Bromo-1H-benzoimidazol-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 5-bromo-2-chloro-1H-benzoimidazole for2-chlorobenzoimidazole in Step A and3,5-dimethyl-1H-4-pryazole-4-carboxylate for ethylpryazole-4-carboxylate in step B. MS (ESI/CI): mass calcd. forC₁₃H₁₁BrN₄O₂, 334.0; m/z found, 335.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):13.21 (br s, 1H), 12.77 (br s, 1H), 7.73 (br s, 1H), 7.51 (br s, 1H),7.36 (dd, J=8.4, 1.6 Hz, 1H), 2.98 (s, 3H), 2.46 (s, 3H).

Example 22:1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 2,5,6-trichloro-1H-benzoimidazole for2-chlorobenzoimidazole in Step A and3,5-dimethyl-1H-4-pryazole-4-carboxylate for ethylpryazole-4-carboxylate in step B. and purified by preparatory HPLC. MS(ESI/CI): mass calcd. for C₁₃H₁₁Cl₂N₄O₂, 325.2; m/z found, 327.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.79 (s, 2H), 2.98 (s, 3H), 2.46 (s, 3H).

Example 23:1-[5-(4-Hydroxy-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 12,substituting 4-hydroxy-phenyl boronic acid for3-(3′-chlorobenzyloxy)phenylboronic acid in Step A. MS (ESI/CI): masscalcd. for C₁₇H₁₂N₄O₃, 320.3; m/z found, 321.1 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆): 12.52-13.80 (br s, 1H), 9.25-10.05 (br s, 1H), 8.84 (s, 1H),8.25 (s, 1H), 7.43-7.80 (m, 5H), 6.86 (d, J=8.6, 2H).

Example 24:1-[5-(3-Hydroxy-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 12,substituting 3-hydroxy-phenyl boronic acid for3-(3′-chlorobenzyloxy)phenylboronic acid in Step A. MS (ESI/CI): masscalcd. for C₁₇H₁₂N₄O₃, 320.3; m/z found, 321.1 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆): 12.50-13.56 (br m, 2H), 9.54 (br s, 1H), 8.91 (s, 1H), 8.30(s, 1H), 7.45-7.88 (br m, 3H), 7.26 (t, J=7.8 Hz, 1H), 7.04-7.14 (m,2H), 6.75 (dd, J=8.0, 1.7 Hz, 1H).

Example 25: 1-(5-Chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 2,5-dichloro-1H-benzoimidazole for 2-chlorobenzoimidazolein Step A. MS (ESI/CI): mass calcd. for C₁₁H₇ClN₄O₂, 262.0; m/z found,263.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD, tautomeric broadening): 8.89 (s,1H), 8.17 (s, 1H), 7.67-7.44 (m, 2H), 7.26 (dd, J=8.6, 1.9 Hz, 1H).

Example 26:1-(5-Bromo-6,7-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 1,substituting 5-bromo-2-chloro-6,7-dimethyl-1H-benzoimidazole for2-chlorobenzoimidazole in Step A. MS (ESI/CI): mass calcd. forC₁₁H₇ClN₄O₂, 334.0; m/z found, 335.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆,tautomeric broadening): 13.51-12.68 (m, 2H), 8.88 (s, 1H), 8.29 (s, 1H),7.80-7.40 (m, 1H), 2.56 (s, 3H), 2.40 (s, 3H).

Example 27: 1-(4-Chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: 3-Chloro-benzene-1,2-diamine. To a solution of3-chloro-2-nitro-phenylamine (1.73 g, 10.0 mmol), NH₄Cl (2.68 g, 50.0mmol), acetone (40 mL) and water (10 mL), was added zinc powderportion-wise (three equal portions over 5 minutes) (3.26 g, 50.0 mmol)at 0° C. The mixture was stirred for 2 h then warmed to 23° C. Themixture was filtered through Celite® and the solvents were concentratedunder reduced pressure. The mixture was re-dissolved in EtOAc/DCM andfiltered a second time through Celite® and the solvents were evaporated.The crude mixture was diluted with EtOAc (100 mL), washed with brine (40mL), dried, filtered, and concentrated under reduced pressure. Theresidue was purified (FCC) (10-50% EtOAc/hexanes) to yield the titledcompound (1.00 g, 70%). MS (ESI/CI): mass calcd. for C₆H₇ClN₂, 142.0;m/z found, 143.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 6.86-6.78 (m, 1H),6.65-6.58 (m, 2H), 3.74 (br s, 2H), 3.46 (br s, 2H).

Step B: 4-Chloro-1,3-dihydro-benzoimidazol-2-one. To a solution of3-chloro-benzene-1,2-diamine (0.820 g, 5.75 mmol) and THF (25 mL), wasadded carbonyl diimidazole (1.12 g, 6.90 mmol) at 0° C. The mixture wasstirred for 16 h and allowed to warm to 23° C. A solution of 1M aqueousHCl (25 mL) was added to the reaction mixture at 0° C., followed bywater (100 mL) and the mixture was stirred for 1 h. The precipitatedsolid was filtered and dried under high vacuum for 18 h to yield thetitled compound, which was used in the next step without furtherpurification (0.800 g, 83%). MS (ESI/CI): mass calcd. for C₇H₅ClN₂O,168.0; m/z found, 169.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 11.13 (s,1H), 10.88 (s, 1H), 7.00-6.86 (m, 3H).

Step C: 2,4-Dichloro-1H-benzoimidazole. Phosphorus oxychloride (10 mL)was added to 4-chloro-1,3-dihydro-benzoimidazol-2-one (0.750 g, 4.45mmol), and the mixture heated to 80° C. for 48 h. The mixture was cooledto 23° C. and POCl₃ removed under reduced pressure. The residue wascooled to 0° C., and cold saturated aqueous NaHCO₃ (20 mL) was addedcautiously. After stirring at 23° C. for 15 min, the mixture wassonicated and the resulting residue was filtered to yield the titledcompound (0.760 g, 92%), which was used in the next step without furtherpurification. MS (ESI/CI): mass calcd. for C₇H₅Cl₂N₂, 186.0; m/z found,187.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 13.68 (s, 1H), 7.51-7.42 (m,1H), 7.32-7.25 (m, 1H), 7.22 (m, 1H).

Step D: 2,4-Dichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole. To amixture of 2,4-dichloro-1H-benzoimidazole (0.550 g, 2.94 mmol) and THF(15 mL) was added DIPEA (1.54 mL, 8.82 mmol) followed by1-chloromethoxy-2-methoxy-ethane (0.550 g, 4.41 mmol) at 23° C. Afterstirring for 18 h, EtOAc (100 mL) was added. The organic layer waswashed with saturated aqueous NaHCO₃ (30 mL) and brine (30 mL). Theorganic layers were combined, dried, filtered, and concentrated underreduced pressure. The residue was purified (FCC) (10-50% EtOAc/hexanesto yield the titled compound as a mixture of regioisomers (0.660 g,82%). MS (ESI/CI): mass calcd. for C₁₁H₁₂Cl₂N₂O₂, 274.0; m/z found,275.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.61 (dd, J=8.0, 1.0 Hz, 1H),7.41 (dd, J=8.1, 0.9 Hz, 1H), 7.33 (dd, J=7.9, 1.0 Hz, 1H), 7.31-7.20(m, 3H), 5.98 (s, 2H), 5.66 (s, 2H), 3.76-3.69 (m, 2H), 3.67-3.60 (m,2H), 3.55-3.46 (m, 4H), 3.37 (s, 3H), 3.36 (s, 3H).

Step E:1-[4-Chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a mixture of2,4-dichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole (0.660 g, 2.40mmol) and DMF (10 mL), was added Cs₂CO₃ (1.88 g, 5.76 mmol) and1H-pyrazole-4-carboxylic acid ethyl ester (0.400 g, 2.88 mmol). Theresulting mixture was then heated to 80° C. for 2 h. The mixture wascooled to 23° C., poured into brine (40 mL), and extracted with EtOAc(3×40 mL). The combined organic layers were washed with brine (40 mL),dried, filtered, and concentrated under reduced pressure. The residuewas purified (FCC) (10-50% EtOAc/hexanes) to yield the titled compoundas a mixture of regioisomers (0.880 g, 97%). MS (ESI/CI): mass calcd.for C₁₇H₁₉ClN₄O₄, 378.1; m/z found, 379.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 8.97 (s, 1H), 8.80 (s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.65 (s,1H), 7.53 (s, 1H), 7.40-7.23 (m, 4H), 6.38 (s, 2H), 6.16 (s, 2H),4.41-4.31 (m, 4H), 3.68-3.59 (m, 2H), 3.57-3.49 (m, 2H), 3.48-3.41 (m,2H), 3.41-3.35 (m, 2H), 3.31 (s, 3H), 3.25 (s, 3H), 1.38 (td, J=7.1, 1.2Hz, 6H).

Step F: 1-(4-Chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acidethyl ester. To a mixture of1-[4-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.370 g, 0.980 mmol) and EtOH (2.5 mL), was added 4MHCl in dioxane (2.5 mL, 10 mmol). The mixture was stirred for 18 h at23° C. The resulting white precipitate was filtered and washed with EtOHto yield the titled compound (0.260 g, 93%). MS (ESI/CI): mass calcd.for C₁₃H₁₁ClN₄O₂, 290.1; m/z found, 291.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 13.83 (s, 1H), 8.98 (s, 1H), 8.45-8.29 (m, 1H), 7.46 (s, 1H),7.38-7.16 (m, 2H), 4.59-4.01 (m, 2H), 1.60-1.01 (m, 3H).

Step G: Preparation of1-(4-Chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To amixture of 1-(4-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester (0.180 g, 0.550 mmol), THF (3 mL), and water (1 mL),was added LiOH.H₂O (95.0 mg, 2.20 mmol). The mixture was stirred 18 h at23° C. The solvent was evaporated, water (3 mL) was added and themixture acidified with aq. 1 M HCl. The resulting white precipitate wasfiltered and dried to yield the titled compound (0.130 g, 90%). MS(ESI/CI): mass calcd. for C₁₁H₇ClN₄O₂, 262.0; m/z found, 263.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): 13.64 (s, 1H), 12.97 (s, 1H), 8.90 (s, 1H),8.30 (s, 1H), 7.48 (d, J=7.4 Hz, 1H), 7.32 (dd, J=7.8, 1.0 Hz, 1H), 7.25(t, J=7.9 Hz, 1H).

Example 28:1-(5-Chloro-7-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 27,substituting 4-chloro-2-nitro-6-trifluoromethyl-phenylamine for3-chloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₂H₆ClF₃N₄O₂, 330.0; m/z found, 331.0 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆): 14.08 (s, 1H), 12.97 (s, 1H), 8.87 (s, 1H), 8.34 (s, 1H), 7.80(s, 1H), 7.64-7.58 (m, 1H).

Example 29:1-(7-Bromo-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 27,substituting 2-bromo-6-nitro-4-trifluoromethoxy-phenylamine for3-chloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₂H₆BrF₃N₄O₃, 390.0; m/z found, 391.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 13.98 (s, 1H), 12.94 (s, 1H), 8.90 (s, 1H), 8.32 (d, J=0.4 Hz,1H), 7.57-7.52 (m, 1H), 7.48 (s, 1H).

Example 30:1-(6-Chloro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 27,substituting 4-chloro-2-nitro-5-trifluoromethyl-phenylamine for3-chloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₂H₆ClF₃N₄O₂, 330.0; m/z found, 331.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 8.93 (s, 1H), 8.34 (s, 1H), 7.99 (s, 1H), 7.85 (s, 1H).

Example 31:1-(4,5,6-Trifluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 27,substituting 2,3,4-trifluoro-6-nitro-phenylamine for3-chloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₁H₅F₃N₄O₂, 282.0; m/z found, 283.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):13.95 (s, 1H), 12.96 (s, 1H), 8.92 (s, 1H), 8.31 (s, 1H), 7.42 (s, 1H).

Example 32:1-(4-Bromo-5,6-difluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 27,Steps B-G, substituting 3-bromo-4,5-difluoro-benzene-1,2-diamine for3-chloro-benzene-1,2-diamine in Step B. MS (ESI/CI): mass calcd. forC₁₁H₅BrF₂N₄O₂, 342.0; m/z found, 343.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 13.93 (s, 1H), 12.93 (s, 1H), 8.88 (s, 1H), 8.30 (s, 1H), 7.55(s, 1H).

Example 33:1-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 27,substituting 4-chloro-2-methyl-6-nitro-phenylamine for3-chloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₂H₉ClN₄O₂, 276.0; m/z found, 277.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):13.77-13.17 (m, 1H), 8.87 (s, 1H), 8.29 (s, 1H), 7.39 (s, 1H), 7.11 (dd,J=1.9, 0.8 Hz, 1H), 2.53 (s, 3H).

Example 34:1-(4,6-Dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 27,substituting 2,4-dichloro-6-nitro-phenylamine for3-chloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₁H₆Cl₂N₄O₂, 296.0; m/z found, 297.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):13.76-13.08 (m, 1H), 8.89 (s, 1H), 8.29 (s, 1H), 7.49 (s, 1H), 7.40 (d,J=1.7 Hz, 1H).

Example 35:1-(4-Bromo-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 27,substituting 2-bromo-6-nitro-4-trifluoromethyl-phenylamine for3-chloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₂H₆BrF₃N₄O₂, 375.0; m/z found, 376.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 14.21 (s, 1H), 13.02 (s, 1H), 8.94 (s, 1H), 8.36 (s, 1H), 7.81(s, 1H), 7.78 (s, 1H).

Example 36:1-(5,6-Difluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 27,Steps D-G, substituting 2-chloro-5,6-difluoro-1H-benzoimidazole (J. Med.Chem. 1997, 40(5), 811-818) for 2,4-dichloro-1H-benzoimidazole in StepD. MS (CI): mass calcd. for C₁₁H₆F₂N₄O₂, 264.1; m/z found, 263.0 [M−H]⁻.¹H NMR (500 MHz, DMSO-d₆): 12.50-14.10 (br m, 2H), 8.86 (s, 1H), 8.28(s, 1H), 7.55-7.66 (br s, 2H).

Example 37:1-(4-Bromo-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 27,substituting 2-bromo-4-chloro-6-nitro-phenylamine for3-chloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₁H₆BrClN₄O₂, 339.9; m/z found, 340.9 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆): 8.72 (s, 1H), 8.00 (s, 1H), 7.36 (d, J=1.8 Hz, 1H), 7.11 (d,J=1.7 Hz, 1H).

Example 38:1-(6-Methanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 27,substituting 4-methanesulfonyl-2-nitro-phenylamine for3-chloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₂H₁₀N₄O₄S, 306.0; m/z found, 307.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆,tautomeric broadening): 13.94 (br s, 1H), 13.02 (br s, 1H), 8.96 (d,J=0.4 Hz, 1H), 8.35 (s, 1H), 8.29-7.60 (m, 3H), 3.24 (s, 3H).

Example 39:1-(6-Chloro-5-cyano-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

Step A: N-(4-Chloro-3-cyano-phenyl)-acetamide. Acetic anhydride (2.79mL, 29.5 mmol), 5-amino-2-chloro-benzonitrile (3.00 g, 19.7 mmol),N,N-dimethylaminopyridine (0.241 g, 1.97 mmol), and toluene (50 mL) werecombined and heated to reflux for 1.5 h. The reaction mixture wascooled, and water and EtOAc (150 mL) were added. The solid remaining inthe mixture was collected and set aside. The aqueous layer was extractedonce more with EtOAc, and the combined layers were washed with brine.The reserved precipitate was then dissolved in EtOAc, which was washedwith brine. All organic layers were combined, dried, filtered, andconcentrated. The residue was triturated with DCM/hexanes to yield thetitled compound (3.52 g, 92% yield). This compound did not yield MSdata. ¹H NMR (400 MHz, CDCl₃): 7.92 (d, J=1.0 Hz, 1H), 7.57 (dd, J=2.1,1.2 Hz, 2H), 2.17 (s, 3H).

Step B: N-(4-Chloro-5-cyano-2-nitro-phenyl)-acetamide.N-(4-Chloro-3-cyano-phenyl)-acetamide (3.00 g, 15.4 mmol) was dissolvedin conc. sulfuric acid (15 mL) and cooled to 0° C. A solution ofpotassium nitrate (3.12 g, 30.8 mmol) in conc. sulfuric acid (15 mL) wasadded drop-wise with stirring. The reaction mixture was kept at 0° C.for 3.5 h, then slowly added to stirred ice/water. The resultingprecipitate was collected, dissolved in EtOAc, dried, filtered, andconcentrated. The residue was purified (FCC) (10-80% EtOAc/hexanes) toyield the titled compound (1.06 g, 29% yield). This compound did notyield MS data. ¹H NMR (400 MHz, CDCl₃): 10.60 (s, 1H), 9.18 (s, 1H),8.58 (s, 1H), 2.36 (s, 3H).

Step C: 4-amino-2-chloro-5-nitro-benzonitrile.N-(4-Chloro-5-cyano-2-nitro-phenyl)-acetamide (1.06 g, 4.415 mmol) wasadded to 2 M HCl (45 mL) and heated to reflux for 2 h, then kept at 60°C. for 16 h. The reaction mixture was cooled and brought to pH 9 withsaturated aqueous sodium bicarbonate. This was extracted with EtOAc(3×50 mL), washed with brine (1×15 mL), dried, filtered, andconcentrated to yield the titled compound (0.868 g, 99%). This compounddid not yield MS data. ¹H NMR (400 MHz, CDCl₃): 8.49 (s, 1H), 7.23 (brs, 2H), 7.02 (s, 1H), 2.40 (s, 3H).

Step D:1-(6-Chloro-5-cyano-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27, substituting 4-amino-2-chloro-5-nitro-benzonitrile for3-chloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₂H₆ClN₅O₂, 287.0; m/z found, 288.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):13.51 (brs, 1H), 8.93 (d, J=0.5 Hz, 1H), 8.33 (d, J=0.4 Hz, 1H), 8.19(s, 1H), 7.84 (s, 1H).

Example 40:1-(6-Chloro-5-nitro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

Step A: 5-Chloro-6-nitro-1,3-dihydro-benzoimidazol-2-one. To a solutionof 4-chloro-5-nitro-benzene-1,2-diamine (8.34 g, 44.4 mmol) and THF (625mL) was added carbonyl diimidazole (8.65 g, 53.3 mmol) at 0° C. Thereaction mixture was allowed to warm to 23° C. and was stirred for 20 hat this temperature. The reaction mixture was concentrated to a volumeof 300 mL and 500 mL aqueous 1M HCl was added, followed by water (totalvolume 2 L). The resulting suspension was cooled at 0° C. for 2 h, andthe precipitate was collected and dried on the filter. It was thentriturated with cold EtOAc (20 mL) and rinsed EtOAc (2×5 mL) to yieldthe titled compound (7.26 g, 76% yield). MS (ESI/CI): mass calcd. forC₇H₄ClN₃O₃, 213.0; m/z found, 214.0 [M+H]⁺.

Step B: 2,6-Dichloro-5-nitro-1H-benzoimidazole. To5-chloro-6-nitro-1,3-dihydro-benzoimidazol-2-one (5.63 g, 26.35 mmol)was added phosphorus oxychloride (35 mL) and the reaction mixture washeated to 85° C. for 36 h. The reaction mixture was concentrated and theresidue triturated with cold saturated aqueous sodium bicarbonate (to pH8, 0.8 L). The resulting precipitate was collected and dried to yieldthe titled compound (5.43 g, 89% yield). MS (ESI/CI): mass calcd. forC₇H₃Cl₂N₃O₂, 231.0; m/z found, 232.0 [M+H]⁺.

Step C:2,6-Dichloro-1-(2-methoxy-ethoxymethyl)-5-nitro-1H-benzoimidazole. To astirred solution of 2,6-dichloro-5-nitro-1H-benzoimidazole (5.43 g, 23.4mmol), diisopropylethylamine (12.2 mL, 70.2 mmol), and THF (120 mL) wasadded portionwise 1-chloromethoxy-2-methoxy-ethane (3.30 mL, 28.1 mmol).The reaction mixture was stirred for 2.5 h and concentrated. Water (50mL) was added to the residue, the mixture was extracted with EtOAc(3×125 mL). The combined organic layers were washed with brine (100 mL),dried, filtered, and concentrated under reduced pressure. The residuewas purified (FCC) (20-55% EtOAc/hexanes) to yield the titled compound(6.23 g, 83% yield) as a 1:1 mixture of regioisomers. MS (ESI/CI): masscalcd. for C₁₁H₁₁Cl₂N₃O₄, 319.0; m/z found, 320.0 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 8.24 (s, 1H), 8.16 (s, 1H), 7.83 (s, 1H), 7.69 (s, 1H),5.71 (s, 2H), 5.68 (s, 2H), 3.72-3.64 (m, 4H), 3.57-3.50 (m, 4H), 3.35(s, 3H), 3.35 (s, 3H).

Step D:1-[6-Chloro-1-(2-methoxy-ethoxymethyl)-5-nitro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a solution of2,6-dichloro-1-(2-methoxy-ethoxymethyl)-5-nitro-1H-benzoimidazole (6.15g, 19.2 mmol), 1H-pyrazole-4-carboxylic acid ethyl ester (2.96 g, 21.1mmol) and DMF (40 mL) was added cesium carbonate (12.5 g, 38.4 mmol) ina sealable pressure vessel. The vessel was purged with nitrogen, sealed,and heated at 60° C. for 2 h. The reaction mixture was poured into a 1:1mixture of brine/water (80 mL), and was extracted with EtOAc (3×125 mL).The combined organic layers were washed with brine (3×125 mL), dried,filtered, and concentrated under reduced pressure. The residue waspurified (FCC) (5-45% EtOAc/hexanes) to yield the titled compound (8.09g, 98%) as a mixture of regioisomers. MS (ESI/CI): mass calcd. forC₁₇H₁₈ClN₅O₆, 423.1; m/z found, 424.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.93 (d, J=0.6 Hz, 1H), 8.28 (s, 1H), 8.22 (d, J=0.6 Hz, 1H), 7.83 (s,1H), 6.26 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.73-3.67 (m, 2H), 3.49-3.44(m, 2H), 3.29 (s, 3H), 1.39 (t, J=7.1 Hz, 3H).

Step E:1-(6-Chloro-5-nitro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27, Steps F-G. MS (ESI/CI): mass calcd. for C₁₁H₆ClN₅O₄, 307.0; m/zfound, 308.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆, tautomeric broadening):14.14 (br s, 1H), 13.03 (br s, 1H), 8.94 (s, 1H), 8.57-7.52 (m, 3H).

Example 41:1-(5-Amino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

Step A.1-[5-Amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a solution of1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-nitro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate D from Example 40) (7.88 g, 18.6 mmol),ammonium chloride (14.9 g, 0.279 mol), acetone (75 mL), and water (15mL) at 0° C. was added portion-wise zinc dust (12.2 g, 0.186 mol). Thereaction mixture was removed from the ice bath and after 15 min, thereaction mixture was filtered through Celite®/diatomaceous earth andrinsed with EtOAc. The filtrate was concentrated and the remainder waspartitioned between EtOAc (300 mL) and saturated aqueous sodiumbicarbonate (55 mL). The aqueous layer was further extracted with EtOAc(2×125 mL). The combined organic layers were washed with brine (2×40mL), dried, filtered, and concentrated under reduced pressure. Theresidue was purified (FCC) (5-65% EtOAc/hexanes) to yield the titledcompound (6.29 g, 86% yield) as a 1:1 mixture of regioisomers. MS(ESI/CI): mass calcd. for C₁₇H₂₀ClN₅O₄, 393.1; m/z found, 394.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.83 (d, J=0.6 Hz, 1H), 8.78 (d, J=0.6 Hz, 1H),8.16 (dd, J=1.9, 0.6 Hz, 2H), 7.63 (s, 1H), 7.54 (s, 1H), 7.09 (s, 1H),6.96 (s, 1H), 6.03 (s, 2H), 6.00 (s, 2H), 4.35 (q, J=7.1 Hz, 4H), 4.18(s, 2H), 4.07 (s, 2H), 3.66-3.60 (m, 4H), 3.49-3.42 (m, 4H), 3.32 (s,3H), 3.31 (s, 3H), 1.37 (t, J=7.1 Hz, 6H).

Step B:1-(5-Amino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27, Steps F-G. MS (ESI/CI): mass calcd. for C₁₁H₈ClN₅O₂, 277.0; m/zfound, 278.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.90 (brs, 1H), 8.81(s, 1H), 8.25 (s, 1H), 7.47 (s, 1H), 6.98 (s, 1H).

Example 42: 1-(5-Fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 27,Steps B-G, substituting 4-fluoro-benzene-1,2-diamine for3-chloro-benzene-1,2-diamine in Step B. MS (ESI/CI): mass calcd. forC₁₁H₇FN₄O₂, 246.1; m/z found, 247.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):13.47 (s, 1H), 12.94 (s, 1H), 8.88 (s, 1H), 8.29 (s, 1H), 7.54 (br s,1H), 7.39 (br s, 1H), 7.13-7.07 (m, 1H).

Example 43:1-(6-Chloro-5-pyrrolidin-1-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: 4-chloro-2-nitro-5-pyrrolidin-1-yl-phenylamine. Pyrrolidine (6mL) was added to 4,5-dichloro-2-nitro-phenylamine (2.58 g, 12.5 mmol) ina sealed tube and the mixture heated to 100° C. for 6 h. The mixture wascooled to 23° C., poured into water (100 mL) and extracted with EtOAc(3×100 mL). The combined organic layers were washed with brine (50 mL),dried, filtered, and concentrated under reduced pressure to afford thetitled compound (3.00 g, 99%). MS (ESI/CI): mass calcd. forC₁₀H₁₂ClN₃O₂, 241.1; m/z found, 242.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.08 (s, 1H), 6.06 (s, 2H), 5.82 (s, 1H), 3.58 (ddd, J=6.6, 4.2, 2.7 Hz,4H), 2.02-1.90 (m, 4H).

Step B: 6-chloro-5-pyrrolidin-1-yl-1H-benzoimidazole. Formic acid (2.9mL) was added to a mixture of4-chloro-2-nitro-5-pyrrolidin-1-yl-phenylamine (0.240 g, 1.00 mmol) andSnCl₂.H₂O (0.680 g, 3.00 mmol), and the mixture was heated to 130° C. ina microwave reactor for 5 min. Six reactions were performed on the samescale. The combined crude mixture was filtered and washed with EtOAc(100 mL). The organic layer was treated with water (25 mL) andneutralized with aqueous 6M NaOH. The aqueous layer was extracted withEtOAc (3×30 mL). The combined organic layers were washed with brine (50mL), dried, filtered, and concentrated under reduced pressure. Theresidue was triturated with EtOAc and the solid was collected to yieldthe titled compound (1.08 g, 70%) as the formate salt. MS (ESI/CI): masscalcd. for C₁₁H₁₂ClN₃, 221.1; m/z found, 222.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 12.84-12.16 (br s, 1H), 8.13 (s, 1H), 8.11 (s, 1H), 7.59 (s,1H), 7.20 (s, 1H), 3.20 (t, J=6.3 Hz, 4H), 2.06-1.66 (m, 4H).

Step C:5-chloro-1-(2-methoxy-ethoxymethyl)-6-pyrrolidin-1-yl-1H-benzoimidazole.To a mixture of 6-chloro-5-pyrrolidin-1-yl-1H-benzoimidazole (0.443 g,2.00 mmol) and THF (5 mL) was added NaH (96.0 mg, 60% dispersion inmineral oil, 2.40 mmol) at 0° C. After stirring the reaction mixture for30 min at 0° C., 1-chloromethoxy-2-methoxy-ethane (0.299 g, 2.40 mmol)was added and the mixture was stirred for 18 h. The reaction mixture wasquenched with water and the aqueous layer was extracted with EtOAc (3×50mL). The combined organic layers were washed with brine (2×20 mL),dried, filtered, and concentrated under reduced pressure. The residuewas purified (FCC) (0-10% MeOH/DCM) to yield the titled compound as amixture of regioisomers (0.240 g, 39%) with a purity of 90%. MS(ESI/CI): mass calcd. for C₁₅H₂₀ClN₃O₂, 309.1; m/z found, 310.1 [M+H]⁺.

Step D:2,5-Dichloro-1-(2-methoxy-ethoxymethyl)-6-pyrrolidin-1-yl-1H-benzoimidazole.A solution of5-chloro-1-(2-methoxy-ethoxymethyl)-6-pyrrolidin-1-yl-1H-benzoimidazole(0.221 g, 0.714 mmol) and THF (2.5 mL) was cooled to −78° C. in anacetone/dry ice bath. Lithium diisopropylamide (2.0M solution inTHF/heptane/ethylbenzene, 0.90 mL, 1.8 mmol) was added dropwise and thereaction mixture was stirred at −78° C. for 30 min. N-chlorosuccinimide(267 mg, 2.00 mmol) was added at −78° C. and the reaction mixture waswarmed to 23° C. and stirred for 2 h. Saturated aqueous NH₄Cl (20 mL)was added and the crude product was extracted into EtOAc (3×50 mL). Thecombined organic layers were washed with brine (50 mL), dried, filtered,and concentrated under reduced pressure. The residue was purified (FCC)(0-100% EtOAc/hexanes) to yield the titled compound (0.240 g, 71%) as amixture of regioisomers with purity of 70%. MS (ESI/CI): mass calcd. forC₁₅H₁₉Cl₂N₃O₂, 343.1; m/z found, 344.1 [M+H]⁺.

Step E:1-(6-Chloro-5-pyrrolidin-1-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27, Steps E-G. MS (ESI/CI): mass calcd. for C₁₅H₁₄ClN₅O₂, 331.1; m/zfound, 332.1 [M+H]⁺. ¹H NMR (DMSO-d₆): 13.35 (s, 1H), 12.88 (s, 1H),8.85 (s, 1H), 8.28 (d, J=0.6 Hz, 1H), 7.71 (s, 0.6H), 7.50 (s, 0.4H),7.44 (s, 0.4H), 7.20 (s, 0.6H), 3.83-3.72 (m, 4H), 3.03-2.89 (m, 4H).

Example 44:1-(6-Chloro-5-piperidin-1-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: 4-Chloro-2-nitro-5-piperidin-1-yl-phenylamine: The titledcompound was prepared in a manner analogous to Example 43, substitutingpiperidine for pyrrolidine in Step A. MS (ESI/CI): mass calcd. forC₁₁H₁₄ClN₃O₂, 255.1; m/z found, 256.1 [M+H]⁺.

Step B:1-(6-Chloro-5-piperidin-1-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid: The titled compound was prepared in a manner analogous to EXAMPLE27. MS (ESI/CI): mass calcd. for C₁₆H₁₆ClN₅O₂, 345.1; m/z found, 346.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 8.86 (s, 1H), 8.29 (s, 1H), 7.63 (s,1H), 7.35 (s, 1H), 2.99 (s, 4H), 1.72 (s, 4H), 1.56 (s, 2H).

Example 45:1-(6-Chloro-5-morpholin-4-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: 4-Chloro-5-morpholin-4-yl-2-nitro-phenylamine: The titledcompound was prepared in a manner analogous to Example 43, substitutingmorpholine for pyrrolidine in Step A. MS (ESI/CI): mass calcd. forC₁₀H₁₂ClN₃O₃, 257.1; m/z found, 258.1 [M+H]⁺.

Step B:1-(6-Chloro-5-morpholin-4-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27. MS (ESI/CI): mass calcd. for C₁₅H₁₄ClN₅O₃, 347.1; m/z found, 348.1[M+H]⁺. ¹H NMR (DMSO-d₆): 13.17 (s, 1H), 12.86 (s, 1H), 8.83 (d, J=0.4Hz, 1H), 8.26 (s, 1H), 7.62 (s, 0.7H), 7.43 (s, 0.3H), 7.31 (s, 0.3H),7.08 (s, 0.7H), 3.23 (s, 5H), 1.90 (s, 4H).

Example 46:1-(6-Chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: 4-Chloro-5-methoxy-2-nitro-phenylamine. To a mixture of4,5-dichloro-2-nitro-phenylamine (1.29 g, 6.23 mmol) and dry MeOH (2mL), a 25 wt % solution of sodium methoxide in MeOH (10 mL) was addedand the mixture stirred for 6 h at 100° C. in a sealed tube. The mixturewas cooled to 23° C., poured into water (50 mL), and extracted withEtOAc (3×50 mL). The combined organic layers were washed with brine (25mL), dried, filtered, and concentrated under reduced pressure to affordthe titled compound (0.700 g, 56%). The crude material was used withoutfurther purification in the next reaction.

Step B: 5-Chloro-6-methoxy-1H-benzoimidazole. The titled compound wasprepared in a manner analogous to Example 45, Step B substituting4-chloro-5-methoxy-2-nitro-phenylamine for4-chloro-2-nitro-5-pyrrolidin-1-yl-phenylamine. MS (ESI/CI): mass calcd.for C₈H₇ClN₂O, 182.1; m/z found, 183.1 [M+H]⁺.

Step C: 5-Chloro-6-methoxy-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole.To a mixture of 5-chloro-6-methoxy-1H-benzoimidazole (0.320 g, 1.75mmol) and THF (10 mL), was added DIPEA (0.850 mL, 4.9 mmol) followed by1-chloromethoxy-2-methoxy-ethane (0.310 g, 2.45 mmol) at 23° C. Afterstirring for 18 h, EtOAc (50 mL) was added. The organic layer was washedwith brine (20 mL), dried, filtered, and concentrated under reducedpressure to afford (0.31 g) of crude material which was used withoutfurther purification in the next reaction.

Step D:1-(6-Chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to Example43, Step D-E. MS (ESI/CI): mass calcd. for C₁₂H₉ClN₄O₃, 292.0; m/zfound, 293.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.85 (d, J=0.6 Hz, 1H),8.29 (d, J=0.6 Hz, 1H), 7.63 (s, 1H), 7.23 (s, 1H), 3.90 (s, 3H). NoteSteps D-E refers to another example

Example 47: 2-(4-Carboxy-pyrazol-1-yl)-1H-benzoimidazole-5-carboxylicacid

Step A: 2-(4-ethoxycarbonyl-pyrazol-1-yl)-1-(2-methoxyethoxymethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester. Thetitled compound was prepared in a manner analogous to EXAMPLE 27, StepsB-E substituting 3,4-diamino-benzoic acid methyl ester for3-chloro-benzene-1,2-diamine in Step B, to give a mixture ofregioisomers. MS (ESI/CI): mass calcd. for C₁₉H₂₂N₄O₆, 402.2; m/z found,403.2 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 9.02 (s, 1H), 9.01 (s, 1H),8.40 (s, 2H), 8.39 (s, 1H), 8.29 (s, 1H), 8.03 (dd, J=8.6, 1.4 Hz, 1H),7.98 (dd, J=8.5, 1.4 Hz, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.83 (d, J=8.5 Hz,1H), 6.08 (s, 2H), 6.01 (s, 2H), 4.31 (q, J=7.1 Hz, 4H), 3.91 (s, 3H),3.90 (s, 3H), 3.55-3.52 (m, 4H), 3.33-3.30 (m, 4H), 3.11 (s, 3H), 3.11(s, 3H), 1.32 (t, J=7.1 Hz, 6H).

Step B: 2-(4-carboxy-pyrazol-1-yl)-1H-benzoimidazole-5-carboxylic acid.To a stirred solution of 2-(4-ethoxycarbonyl-pyrazol-1-yl)-1-(2-methoxyethoxymethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (0.150 g,0.373 mmol) and acetic acid (4.5 mL) was added aqueous hydrochloric acid(6M, 4.5 mL). The reaction mixture was heated to 100° C. for 18 h andthen cooled to 23° C. The resulting precipitate was collected to yieldthe titled compound (0.30 mg, 30% yield). MS (ESI/CI): mass calcd. forC₁₂H₈N₄O₄, 272.1; m/z found, 273.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆):8.94 (s, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.87 (dd, J=8.4, 1.5 Hz, 1H),7.63 (d, J=8.4 Hz, 1H).

Example 48:1-(5-Bromo-7-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

Step A: 5-Bromo-3-fluoro-benzene-1,2-diamine. To a solution of5-bromo-3-fluoro-2-nitro-phenylamine (2 g, 8.5 mmol), NH₄Cl (6.81 g,127.6 mmol), acetone (100 mL) and water (20 mL), was added zinc powderportion-wise (three equal portions over 5 minutes) (8.34 g, 127.6 mmol)at 0° C. The mixture was stirred for 2 h then warmed to 23° C. Themixture was filtered through Celite® and the solvents were concentratedunder reduced pressure. The mixture was re-dissolved in EtOAc/DCM andfiltered a second time through Celite® and the solvents were evaporated.The crude mixture was diluted with EtOAc (200 mL), washed with brine (40mL), dried, filtered, and concentrated under reduced pressure. Theresultant residue was used in the next reaction without furtherpurification.

Step B:1-(5-Bromo-7-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE47, substituting 5-bromo-3-fluoro-benzene-1,2-diamine for3-chloro-benzene-1,2-diamine in Step A. MS (ESI/CI): mass calcd. forC₁₁H₆BrFN₄O₂, 324.0; m/z found, 325.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆):8.88 (s, 1H), 8.30 (s, 1H), 7.45 (dd, J=9.5, 2.3 Hz, 1H), 7.34 (d, J=7.6Hz, 1H).

Example49:1-(5-Bromo-7-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 47substituting 5-bromo-3-methyl-benzene-1,2-diamine for3-chloro-benzene-1,2-diamine in Step A. MS (ESI/CI): mass calcd. forC₁₂H₉BrN₄O₂, 320.0; m/z found, 321.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆):8.88 (s, 1H), 8.29 (s, 1H), 7.53 (s, 1H), 7.23 (s, 1H), 2.53 (s, 3H).

Example 50:1-[5-(3,4-Dichloro-phenoxy)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

Step A: 5-(3,4-Dichloro-phenoxy)-2-nitro-4-trifluoromethyl-phenylamine.To a mixture of 5-chloro-2-nitro-4-trifluoromethyl-phenylamine (1.00 g,4.16 mmol) and DMA (21 mL) was added K₂CO₃ (1.15 g, 8.32 mmol) and3,4-dichloro-phenol (1.36 g, 8.32 mmol). The mixture was heated to 85°C. for 18 h. The mixture was cooled to 23° C. and poured into ice water.The precipitate was collected, dissolved in EtOAc (150 mL) and washedwith brine (2×30 mL). The organic layers were combined, dried, filtered,and concentrated under reduced pressure to yield the titled compound(1.51 g, 99%). ¹H NMR (500 MHz, CDCl₃): 8.52 (s, 1H), 7.53 (d, J=8.7 Hz,1H), 7.26 (d, J=3.2 Hz, 1H), 7.00 (dd, J=8.7, 2.7 Hz, 1H), 6.37 (s, 2H),6.06 (s, 1H).

Step B:1-[5-(3,4-Dichloro-phenoxy)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27. MS (ESI/CI): mass calcd. for C₁₈H₉Cl₂F₃N₄O₃, 456.0; m/z found, 457.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.29 (s, 2H), 8.90 (d, J=0.4 Hz,1H), 8.32 (s, 1H), 7.96 (s, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.38 (s, 1H),7.33 (d, J=2.8 Hz, 1H), 7.01 (dd, J=8.9, 2.9 Hz, 1H).

Example 51:1-[6-Chloro-5-(4-chloro-phenoxy)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 50,substituting 4-chloro-phenol for 3,4-dichloro-phenol and4,5-dichloro-2-nitro-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₇H₁₀Cl₂N₄O₃, 388.0; m/z found, 389.0 [M+H]⁺. ¹H NMR(DMSO-d₆): 13.25 (br s, 2H), 8.88 (s, 1H), 8.29 (s, 1H), 7.78 (s, 1H),7.50-7.22 (m, 3H), 7.04-6.80 (m, 2H).

Example 52:1-[5-(4-Chloro-phenoxy)-6-trifluoromethoxy-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 50,substituting 4-chloro-phenol for 3,4-dichloro-phenol and5-chloro-2-nitro-4-trifluoromethoxy-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₆H₁₀ClF₃N₄O₄, 438.0; m/z found, 439.0 [M+H]⁺. ¹H NMR(DMSO-d₆): 8.82 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.41 (d, J=9.0 Hz,2H), 7.33 (s, 1H), 6.99 (d, J=9.0 Hz, 2H).

Example 53:1-(5-Phenoxy-6-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 50,substituting phenol for 3,4-dichloro-phenol and5-chloro-2-nitro-4-trifluoromethoxy-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₈H₁₁F₃N₄O₄, 404.1; m/z found, 405.1 [M+H]⁺. ¹H NMR(DMSO-d₆): 13.30 (s, 1H), 8.88 (s, 1H), 8.30 (s, 1H), 7.72 (s, 1H),7.48-7.34 (m, 2H), 7.27 (s, 1H), 7.14 (t, J=7.4 Hz, 1H), 7.00 (d, J=7.9Hz, 2H).

Example 54:1-[5-(4-Fluoro-phenoxy)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 50,substituting 4-fluoro-phenol for 3,4-dichloro-phenol in Step A. MS(ESI/CI): mass calcd. for C₁₈H₁₀F₄N₄O₃, 406.1; m/z found, 407.1 [M+H]⁺.¹H NMR (DMSO-d₆): 13.30 (s, 2H), 8.87 (s, 1H), 8.29 (s, 1H), 7.93 (s,1H), 7.31-7.18 (m, 2H), 7.10 (ddd, J=6.7, 5.4, 3.1 Hz, 3H).

Example 55:1-[5-(4-Chloro-phenoxy)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 50,substituting 4-chloro-phenol for 3,4-dichloro-phenol in Step A. MS(ESI/CI): mass calcd. for C₁₈H₁₀ClF₃N₄O₃, 422.0; m/z found, 423.0[M+H]⁺. ¹H NMR (DMSO-d₆): 8.81 (s, 1H), 8.18 (s, 1H), 7.87 (s, 1H),7.50-7.32 (m, 2H), 7.18 (s, 1H), 7.07-6.91 (m, 2H).

Example 56:1-(5-Phenoxy-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 50,substituting phenol for 3,4-dichloro-phenol in Step A. MS (ESI/CI): masscalcd. for C₁₈H₁₁F₃N₄O₃, 388.1; m/z found, 389.1 [M+H]⁺. ¹H NMR(DMSO-d₆): 13.32 (s, 2H), 8.87 (s, 1H), 8.28 (s, 1H), 7.93 (s, 1H), 7.41(t, J=7.9 Hz, 2H), 7.16 (dd, J=16.1, 8.7 Hz, 2H), 7.04 (d, J=8.0 Hz,2H).

Example 57:1-(6-Chloro-5-phenoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: 5-Chloro-2-nitro-4-phenoxyphenylamine. To a solution of phenol(0.500 g, 5.31 mmol) in dry DMF (20 mL) was added solid sodiumt-butoxide (0.510 g, 5.31 mmol). The mixture was heated to 100° C. for60 min, then 4,5-dichloro-2-nitro-phenylamine (1.00 g, 4.83 mmol) wasadded and the reaction mixture was heated at 100° C. for 19 h. Thereaction mixture was allowed to cool to ambient temperature. Thereaction mixture was added to water and extracted with EtOAc. Thecombined organic layers were washed with 1M Na₂CO₃, dried, filtered, andconcentrated under reduced pressure. The residue was purified (FCC)(hexanes:EtOAc, 5% to 30% over 20 minutes) to yield the titled compoundas an orange solid (0.821 g, 64%). ¹H NMR (400 MHz, CDCl₃): 8.27 (s,1H), 7.50-7.34 (m, 2H), 7.27 (d, J=8.9 Hz, 2H), 7.10 (dd, J=8.6, 1.1 Hz,2H), 6.02 (s, 3H).

Step B: 6-Chloro-5-phenoxy-1H-benzoimidazole. To a solution of5-chloro-2-nitro-4-phenoxyphenylamine (0.810 g, 3.06 mmol) in DMF (12mL) was added trimethylorthoformate (12 mL) followed by sodiumdithionite (2.66 g, 15.3 mmol), and glacial acetic acid (1.5 mL). Thereaction mixture was heated in a sealed tube at 100° C. for 14 h.Additional sodium dithionite (0.5 g) and acetic acid (1 mL) were addedand heating was continued at 120° C. for an additional 3 h. The reactionflask was cooled in ice, added cautiously to half-saturated sodiumbicarbonate solution (300 mL) and extracted with EtOAc. Combined organiclayers were washed with 5% NaHCO₃, brine, dried, filtered, andconcentrated under reduced pressure. The residue was purified (FCC)(hexanes:EtOAc, 0% to 5% over 20 minutes) to yield the titled compoundas a yellow amorphous solid (0.57 g, 76%) as a mixture of tautomers. MS(ESI/CI): mass calcd. for C₁₃H₉ClN₂O, 244; m/z found, 245 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 9.55 (s, 1H), 8.06 (s, 1H), 8.0-7.2 (m, 2H), 7.32 (t,J=7.9 Hz, 2H), 7.09 (t, J=7.3 Hz, 1H), 6.96 (d, J=8.3 Hz, 2H).

Step C: 6-Chloro-1-(2-methoxy-ethoxymethyl)-5-phenoxy-1H-benzoimidazole.To a solution of 6-chloro-5-phenoxy-1H-benzoimidazole (0.565 g, 2.31mmol) and diisopropylethylamine (0.890 mL, 5.08 mmol) in dry DMF (10 mL)was added MEM chloride (0.29 mL, 2.54 mmol) at 0° C. After 3 d atambient temperature, the reaction mixture was added to saturated NH₄Cl(100 mL) and extracted with EtOAc. Combined organic layers were washedwith 0.5 M citric acid, 5% NaHCO₃, brine, and dried, filtered, andconcentrated under reduced pressure. The residue was purified (FCC)(DCM:MeOH, 0% to 5% over 10 min) to yield the title compound as a redoil that was a 1:1 mixture of regioisomers (0.563 g, 73%). This materialwas used directly in the next step.

Step D:2,6-Dichloro-1-(2-methoxy-ethoxymethyl)-5-phenoxy-1H-benzoimidazole. Toa solution of diisopropylamine (260 LL, 1.85 mmol) in dry THF (2 mL)cooled in −78° C. bath was added n-buthyllithium in hexanes (1.16 mL ofa 1.6 M solution). After 45 min, the contents of the flask were addedvia syringe to a −78° C. solution of6-chloro-1-(2-methoxy-ethoxymethyl)-5-phenoxy-1H-benzoimidazole (0.560g, 1.68 mmol) in dry THF (2 mL). After 60 min, N-chlorosuccinimide(0.247 g, 1.85 mmol) in THF (3 mL) was added via syringe to the darksolution at which time the color changed to light brown. The reactionmixture was allowed to warm to ambient temperature then was added tosaturated aq. NH₄Cl and extracted with EtOAc. The combined organiclayers were washed with 0.5 M citric acid, 5% aq. NaHCO₃, brine, dried,filtered, and concentrated under reduced pressure. The residue waspurified (FCC) to yield the titled compound as a mixture of regioisomers(0.251 g, 41%; orange oil). MS (ESI/CI): mass calcd. for C₁₇H₁₆Cl₂N₂O₃,366; m/z found, 367 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.62(s, 1H), 7.37 (s, 1H), 7.36-7.29 (m, 4H), 7.18 (s, 1H), 7.14-7.04 (m,2H), 6.98-6.90 (m, 4H), 5.63 (s, 2H), 5.54 (s, 2H), 3.72-3.63 (m, 2H),3.63-3.57 (m, 2H), 3.57-3.50 (m, 2H), 3.49-3.42 (m, 2H), 3.38 (s, 3H),3.28 (s, 3H).

Step E:1-(6-Chloro-5-phenoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester. To a stirred solution of2,6-dichloro-1-(2-methoxy-ethoxymethyl)-5-phenoxy-1H-benzoimidazole(0.251 g, 0.684 mmol) and ethyl pyrazole-4-carboxylate (0.115 g, 0.820mmol) in dry DMF (4 mL) was added anhydrous cesium carbonate (0.535 g,1.64 mmol). The stirred suspension was heated in 80° C. bath in a sealedtube for 2 h. After coming to ambient temperature, the reaction mixturewas added to ice water (100 mL), acidified with 1N HCl (3 mL) andextracted with dichloromethane. The combined organic layers were washedwith water, brine, dried, filtered, and concentrated under reducedpressure to afford the titled product as a crude orange paste (0.361 g).MS (ESI/CI): mass calcd. for C₂₃H₂₃ClN₄O₅, 470; m/z found, 471 [M+H]⁺.

Step F:1-(6-Chloro-5-phenoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid.1-(6-Chloro-5-phenoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester (0.361 g) was dissolved in glacial acetic acid (9 mL)and 6N HCl (9 mL) and heated in a sealed tube at 100° C. for 6 h. Aftercooling in ice, water (5 mL) was added and the solids were collected viafiltration, washed with water, and dried under vacuum (60° C., 10 mmHg).The resulting tan powder was recrystallized from MeOH:water (10 mL,10:1), collected via filtration and dried under reduced pressure toafford the title compound as a tan solid (115 mg, 90%). Mp=134-138° C.(dec.). MS (ESI/CI): mass calcd. for C₁₇H₁₁ClN₄O₃, 354; m/z found, 355[M+H]⁺, 396 [MH+MeCN]⁺. ¹H NMR (mixture of tautomers) (500 MHz,DMSO-d6): 13.60 (s, 0.5H), 13.50 (s, 0.5H), 12.93 (s, 1H), 8.89 (s, 1H),8.30 (s, 1H), 7.90 (s, 0.5H), 7.65 (s, 0.5H), 7.42 (m, 2.5H), 7.15 (m,1.5H), 7.02-6.75 (m, 2H).

Example 58:1-(5-Bromo-7-methyl-1H-imidazo[4,5-f]quinolin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to Example 57steps B-F substituting 8-bromo-2-methyl-6-nitro-quinolin-5-ylamine for5-chloro-2-nitro-4-phenoxyphenylamine in Step B. MS (ESI/CI): masscalcd. for C₁₅H₁₀BrN₅O₂, 371.0; m/z found, 372.0 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 8.94 (s, 1H), 8.83 (d, J=8.3 Hz, 1H), 8.33 (s, 1H), 8.28(s, 1H), 7.62 (d, J=8.4 Hz, 1H), 2.74 (s, 3H).

Example 59:1-(5-Benzyloxy-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: Preparation of 5-benzyloxy-4-chloro-2-nitro-phenylamine. Benzylalcohol (12.5 mL, 0.121 mol), 4,5-dichloro-2-nitro-phenylamine (5.00 g,24.2 mmol), cesium carbonate (15.7 g, 48.3 mmol), and DMA (110 mL) werecombined in a sealable pressure vessel. The vessel was purged with drynitrogen, sealed, and heated at 80° C. for 17 h. The reaction mixturewas poured into brine (400 mL) and cooled to 0° C. The resultingprecipitate was collected and dissolved in EtOAc (400 mL). The organiclayer was washed with water (50 mL) and brine (50 mL). The organiclayers were combined, dried, filtered, and concentrated under reducedpressure. The residue was purified (FCC) (1-50% EtOAc/hexanes,dryloaded) to yield the titled compound (2.47 g, 37% yield). MS(ESI/CI): mass calcd. for C₁₃H₁₁ClN₂O₃, 278.1; m/z found, 279.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.20 (s, 1H), 7.50-7.30 (m, 5H), 6.23 (s, 1H),6.19 (br s, 2H), 5.16 (s, 2H).

Step B:1-(5-Benzyloxy-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27. MS (ESI/CI): mass calcd. for C₁₈H₁₃ClN₄O₃, 368.1; m/z found, 369.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomeric broadening): 13.45-13.28(m, 1H), 12.93 (br s, 1H), 8.84 (s, 1H), 8.27 (s, 1H), 7.81-7.13 (m,7H), 5.25 (s, 2H).

Example 60:1-(6-Chloro-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: 4-chloro-2-nitro-5-m-tolylsulfanyl-phenylamine. A mixture of3-methyl-benzenethiol (2.30 mL, 19.3 mmol),4,5-dichloro-2-nitro-phenylamine (2.00 g, 9.66 mmol), potassiumcarbonate (2.67 g, 19.3 mmol), and DMF (48 mL) was heated at 90° C. for16 h. The reaction mixture was cooled to 23° C. EtOAc was added and theorganic layer was washed with saturated aqueous NaHCO₃ (2×80 mL) andbrine (lx 80 mL). The aqueous layers were extracted with EtOAc (3×80mL). The organic layers were combined, dried, filtered, and concentratedunder reduced pressure. The residue was purified (FCC) (0-100%EtOAc/hexanes) to yield the titled compound (2.30 g, 81%). ¹H NMR (400MHz, CDCl₃): 8.12 (s, 1H), 7.41-7.36 (m, 3H), 7.34-7.30 (m, 1H), 5.95(s, 1H), 5.88 (br s, 2H), 2.41 (s, 3H).

Step B: Preparation of 4-chloro-5-m-tolylsulfanyl-benzene-1,2-diamine.To an ice bath cooled solution (0° C.) of4-chloro-2-nitro-5-m-tolylsulfanyl-phenylamine (2.30 g, 7.80 mmol),ammonium chloride (6.26 g, 117 mmol), acetone (32.5 mL), and water (6.5mL) was added portion-wise zinc powder (5.10 g, 78.0 mmol). The reactionmixture was removed from the ice bath and after 30 min, the reactionmixture was filtered through a pad of Celite® and washed with EtOAc. Thefiltrate was placed in a sep funnel and the organic layer was collected.The organic layers dried, filtered, and concentrated under reducedpressure. The crude material was used without further purification inthe next reaction.

Step C: Preparation of 6-chloro-5-m-tolylsulfanyl-1H-benzoimidazole. Toa cooled (0° C.) solution of4-chloro-5-m-tolylsulfanyl-benzene-1,2-diamine (2.07 g, 7.80 mmol) andtrimethyl orthoformate (5.81 mL, 53.0 mmol) was added concentrated HCl(0.722 mL, 11.5 mmol). The reaction mixture was warmed to 23° C. over 16h, then concentrated under reduced pressure. EtOAc (100 mL) was added tothe crude product and the organic layer was washed with saturatedaqueous NaHCO₃ (2×75 mL). The aqueous layer was extracted with EtOAc(2×50 mL). The organic layers were combined, dried, filtered, andconcentrated under reduced pressure. The crude material was used in thenext step without further purification. MS (ESI/CI): mass calcd. forC₁₄H₁₁ClN₂S, 274.0; m/z found, 275.1 [M+H]⁺.

Step D:6-chloro-1-(2-methoxy-ethoxymethyl)-5-m-tolylsulfanyl-1H-benzoimidazole.To a cooled solution (0° C.) of6-chloro-5-m-tolylsulfanyl-1H-benzoimidazole (2.14 g, 7.78 mmol) and THF(39 mL) was added DIPEA (2.71 mL, 15.6 mmol).1-Chloromethoxy-2-methoxy-ethane (0.977 mL, 8.56 mmol) was addeddropwise, and the reaction mixture was allowed to warm to 23° C. over 16h. The reaction mixture was concentrated. The residue was purified (FCC)(0-100% EtOAc/hexanes) to yield the titled compound (1.89 g, 67%) as a1:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C₁₈H₁₉ClN₂O₂S,362.1; m/z found, 363.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.95 (s, 1H),7.92 (s, 1H), 7.88 (s, 1H), 7.64 (s, 1H), 7.59 (s, 1H), 7.41 (s, 1H),7.22-7.18 (m, 3H), 7.16-7.13 (m, 2H), 7.11-7.05 (m, 3H), 5.56 (s, 2H),5.47 (s, 2H), 3.57-3.54 (m, 2H), 3.52-3.49 (m, 2H), 3.48-3.45 (m, 2H),3.44-3.42 (m, 2H), 3.35 (s, 3H), 3.30 (s, 3H), 2.30 (s, 6H).

Step E:2,6-dichloro-1-(2-methoxy-ethoxymethyl)-5-m-tolylsulfanyl-1H-benzoimidazole.A solution of6-chloro-1-(2-methoxy-ethoxymethyl)-5-m-tolylsulfanyl-1H-benzoimidazole(1.89 g, 5.21 mmol) and THF (13 mL) was cooled to −78° C. in anacetone/dry ice bath. Buthyllithium (2.2M solution in hexanes, 2.60 mL,5.73 mmol) was added dropwise and the reaction mixture was stirred at−78° C. for 1 h. (Lithium diisopropylamide as a 2.0M solution inTHF/heptane/ethylbenzene can also be used as a base.) A solution ofN-chlorosuccinimide (765 mg, 5.73 mmol) and THF (11.5 mL) was added. Thereaction mixture was warmed to 23° C. and stirred for 2 h. Saturatedaqueous NH₄Cl (20 mL) was added and the crude product was extracted intoCH₂Cl₂ (3×75 mL). The organic layers were dried, filtered, andconcentrated under reduced pressure. The residue was purified (FCC)(0-100% EtOAc/hexanes) to provide the titled compound (1.46 g, 71%) as a1:1 mixture of regioisomers. MS (ESI/CI): mass calcd. forC₁₈H₁₈Cl₂N₂O₂S, 396.0; m/z found, 397.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.74 (s, 1H), 7.57 (s, 1H), 7.40 (s, 1H), 7.29 (s, 1H), 7.23-7.18 (m,3H), 7.18-7.14 (m, 2H), 7.12-7.07 (m, 3H), 5.58 (s, 2H), 5.48 (s, 2H),3.64-3.60 (m, 2H), 3.54-3.48 (m, 4H), 3.43-3.40 (m, 2H), 3.34 (s, 3H),3.29 (s, 3H), 2.30 (s, 6H).

Step F:1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a mixture of2,6-dichloro-1-(2-methoxy-ethoxymethyl)-5-m-tolylsulfanyl-1H-benzoimidazole(0.500 g, 1.26 mmol) and DMF (2.52 mL) was added cesium carbonate (0.820g, 2.52 mmol) and 1H-pyrazole-4-carboxylic acid ethyl ester (0.194 g,1.38 mmol). The mixture was heated at 80° C. for 2 h in a sealed tube.The mixture was cooled to 23° C. and poured into brine (40 mL), andextracted with EtOAc (3×50 mL). The organic layers were washed withbrine (40 mL), dried, filtered, and concentrated under reduced pressure.The residue was purified (FCC) (0-50% EtOAc/hexanes) to yield the titledcompound as a 1:1 mixture of regioisomers (0.387 g, 61%). ¹H NMR (500MHz, CDCl₃): 8.84 (s, 1H), 8.79 (s, 1H), 8.14 (s, 2H), 7.77 (s, 1H),7.68 (s, 1H), 7.44 (s, 1H), 7.41 (s, 1H), 7.23-7.18 (m, 4H), 7.18-7.16(m, 1H), 7.12 (d, J=7.6 Hz, 2H), 7.09 (d, J=7.5 Hz, 1H), 6.09 (s, 2H),5.98 (s, 2H), 4.36-4.27 (m, 4H), 3.66-3.60 (m, 2H), 3.55-3.50 (m, 2H),3.48-3.42 (m, 2H), 3.38-3.34 (m, 2H), 3.28 (s, 3H), 3.24 (s, 3H), 2.32(s, 3H), 2.31 (s, 3H), 1.38-1.30 (m, 6H).

Step G:1-(6-chloro-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester. To a mixture of1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.190 g, 0.379 mmol) and EtOH (1 mL) was added 4M HClin dioxane (1 mL). The mixture was stirred for 3 h at 23° C. Thereaction mixture was concentrated and Et₂O (10 mL) was added. The solidswere filtered and washed with Et₂O to yield the titled compound (0.143g, 91%). MS (ESI/CI): mass calcd. for C₂₀H₁₇ClN₄O₂S, 412.1; m/z found,413.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.95 (s, 1H), 8.35 (s, 1H),7.77 (s, 1H), 7.41 (s, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.19-7.14 (m, 2H),7.12-7.06 (m, 1H), 4.30 (q, J=7.1 Hz, 2H), 2.29 (s, 3H), 1.31 (t, J=7.0Hz, 3H).

Step H:1-(6-chloro-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. To a mixture of1-(6-chloro-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester (0.100 g, 0.242 mmol), THF (1 mL), and water (0.3 mL)was added LiOH.H₂O (40.7 mg, 0.969 mmol). The mixture was stirred for 18h at 23° C. The solvent was evaporated, water (3 mL) was added and themixture acidified with 1M HCl. The resulting white precipitate wasfiltered and dried to yield the titled compound (85.0 mg, 89%). MS(ESI/CI): mass calcd. for C₁₈H₁₃ClN₄O₂S, 384.0; m/z found, 385.0 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 8.82 (s, 1H), 8.22 (s, 1H), 7.73 (s, 1H),7.43 (s, 1H), 7.27 (t, J=7.9 Hz, 1H), 7.15-7.10 (m, 2H), 7.04 (d, J=7.9Hz, 1H), 2.27 (s, 3H).

Example 61:1-[6-Chloro-5-(4-chloro-phenylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 60,substituting 4-chloro-benzenethiol for 3-methyl-benzenethiol in Step A,and substituting lithium diisopropylamide for buthyllithium in Step E.MS (ESI/CI): mass calcd. for C₁₇H₁₀Cl₂N₄O₂S, 404.0; m/z found, 405.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 8.84 (s, 1H), 8.23 (s, 1H), 7.76 (s,1H), 7.57 (s, 1H), 7.44-7.40 (m, 2H), 7.23-7.18 (m, 2H).

Example 62:1-(6-Chloro-5-phenylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 60,substituting benzenethiol for 3-methyl-benzenethiol in Step A, andsubstituting lithium diisopropylamide for buthyllithium in Step E. MS(ESI/CI): mass calcd. for C₁₇H₁₁ClN₄O₂S, 370.0; m/z found, 371.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): 12.93 (s, 1H), 8.87 (s, 1H), 8.29 (s, 1H),7.78 (br s, 1H), 7.49-7.37 (m, 3H), 7.37-7.27 (m, 3H).

Example 63:1-[6-Chloro-5-(3,4-dichloro-phenylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 60,substituting 3,4-dichloro-benzenethiol for 3-methyl-benzenethiol in StepA. MS (ESI/CI): mass calcd. for C₁₇H₉Cl₃N₄O₂S, 437.9; m/z found, 438.9[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.82 (s, 1H), 8.17 (s, 1H), 7.78 (s,1H), 7.75 (s, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.06(dd, J=8.5, 2.2 Hz, 1H).

Example 64:1-[6-Chloro-5-(3-methoxy-phenylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 60,substituting 3-methoxy-benzenethiol for 3-methyl-benzenethiol in Step A.MS (ESI/CI): mass calcd. for C₁₈H₁₃ClN₄O₃S, 400.0; m/z found, 401.0[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.87 (d, J=0.5 Hz, 1H), 8.28 (d,J=0.5 Hz, 1H), 7.78 (br s, 1H), 7.50 (br s, 1H), 7.32-7.29 (m, 1H), 6.89(ddd, J=8.3, 2.4, 0.9 Hz, 1H), 6.82-6.79 (m, 2H), 3.72 (s, 3H).

Example 65:1-[6-Chloro-5-(4-methoxy-phenylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 60,substituting 4-methoxy-benzenethiol for 3-methyl-benzenethiol in Step A,and substituting lithium diisopropylamide for buthyllithium in Step E.MS (ESI/CI): mass calcd. for C₁₈H₁₃ClN₄O₃S, 400.0; m/z found, 401.0[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.72 (s, 1H), 8.14 (s, 1H), 7.64 (s,1H), 7.39 (d, J=8.6 Hz, 2H), 7.08 (s, 1H), 7.04 (d, J=8.8 Hz, 2H), 3.80(s, 3H).

Example 66:1-(5-Benzylsulfanyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Method A:

Step A: 5-benzylsulfanyl-4-chloro-2-nitro-phenylamine. To a mixture of4,5-dichloro-2-nitro-phenylamine (3.00 g, 14.5 mmol) and DMF (72 mL) wasadded K₂CO₃ (5.31 g, 29.0 mmol) and phenyl-methanethiol (3.94 g, 31.7mmol). The mixture was heated to 70° C. for 18 h and then cooled to 23°C. The reaction mixture was dissolved in EtOAc (200 mL), washed withsaturated sodium bicarbonate solution (100 mL), washed with brine (3×100mL). The organic layers were combined, dried, filtered, and concentratedunder reduced pressure. The residue was purified (FCC) (5-45%EtOAc/hexanes) to yield the titled compound (2.39 g, 56%). MS (ESI/CI):mass calcd. for C₁₃H₁₁ClN₂O₂S, 294.0; m/z found, 295.0 [M+H]⁺. ¹H NMR(600 MHz, DMSO-d₆): 7.96 (s, 1H), 7.56 (s, 2H), 7.50 (d, J=7.2 Hz, 2H),7.37 (t, J=7.5 Hz, 2H), 7.31 (t, J=7.4 Hz, 1H), 7.05 (s, 1H), 4.27 (s,2H).

Step B:1-[5-benzylsulfanyl-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. The titled compound was prepared in a manner analogousto EXAMPLE 27, Steps A-E substituting5-benzylsulfanyl-4-chloro-2-nitro-phenylamine for3-chloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₂₄H₂₅ClN₄O₄S, 500.1; m/z found, 501.1 [M+H]⁺.

Step C:1-(5-benzylsulfanyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester. To a mixture of1-[5-benzylsulfanyl-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (96.0 mg, 0.192 mmol) and EtOH (5 mL) was added 4M HClin dioxane (5 mL, 20 mmol). The mixture was stirred for 18 h at 23° C.The reaction mixture was concentrated under reduced pressure and theresulting residue was triturated in Et₂O. The resultant suspension wasfiltered and washed with Et₂O to yield the titled compound (69.0 mg,87%). MS (ESI/CI): mass calcd. for C₂₀H₁₇ClN₄O₂S, 412.1; m/z found,413.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 13.53 (d, J=12.3 Hz, 1H), 8.95(s, 1H), 8.35 (s, 1H), 7.78 (s, 0.5H), 7.65 (s, 0.5H), 7.55 (s, 0.5H),7.44 (s, 0.5H), 7.38 (d, J=7.2 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 7.25 (s,1H), 4.32-4.26 (m, 4H), 1.32 (t, J=7.1 Hz, 3H).

Step D:1-(5-benzylsulfanyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. To a mixture of1-(5-benzylsulfanyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester (57.0 mg, 0.127 mmol), THF (2 mL), and water (0.67 mL)was added LiOH.H₂O (27.0 mg, 0.654 mmol). The mixture was stirred for 18h at 23° C. The reaction mixture was concentrated under reducedpressure, water (3 mL) was added and the mixture acidified to pH=3 with1M HCl. The resulting white precipitate was filtered and dried to yieldthe titled compound (39.0 mg, 80%). MS (ESI/CI): mass calcd. forC₁₈H₁₃ClN₄O₂S, 384.0; m/z found, 385.0 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆): 8.86 (s, 1H), 8.29 (s, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.39(d, J=7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 7.25 (t, J=7.1 Hz, 1H), 4.29(s, 2H).

Method B:

Step A:1-[5-tert-butylsulfanyl-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. The titled compound was prepared in a manner analogousto EXAMPLE 66, Method A, Steps A-B, substituting2-methyl-propane-2-thiol for phenyl-methanethiol in Step A to give a 1:1mixture of regioisomers. MS (ESI/CI): mass calcd. for C₂₁H₂₇ClN₄O₄S,466.1; m/z found, 467.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.89-8.88 (m,2H), 8.19 (s, 2H), 8.03 (s, 1H), 7.93 (s, 1H), 7.85 (s, 1H), 7.78 (s,1H), 6.17 (s, 2H), 6.13 (s, 2H), 4.39-4.33 (m, 4H), 3.71-3.64 (m, 4H),3.50-3.42 (m, 4H), 3.31 (s, J=5.1 Hz, 3H), 3.30 (s, 3H), 1.43-1.29 (m,24H).

Step B:1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-(2-nitro-phenyldisulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a stirred solution of1-[5-tert-butylsulfanyl-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (3.00 g, 6.42 mmol) and DCM (32 mL) was added potassiumcarbonate (1.78 g, 12.9 mmol). The reaction mixture was treated with2-nitrobenzenesulfenyl chloride (3.05 g, 16.1 mmol) and stirred at 23°C. for 16 h. The resulting residue was concentrated and purified by FCC(5-30% EtOAc/hexanes) to provide the titled compound (2.99 g, 82% crudeyield) as a 2:1 ratio of regioisomers. This compound was used withoutfurther purification in subsequent reactions. MS (ESI/CI): mass calcd.for C₂₃H₂₂ClN₅O₆S₂, 563.1; m/z found, 564.1 [M+H]+. ¹H NMR (600 MHz,CDCl₃): 8.85-8.82 (m, 2H), 8.17 (s, 2H), 7.75 (s, 0.66H), 7.72 (s,1.34H), 7.68 (s, 1.34H), 7.64 (s, 0.66H), 7.45-7.42 (m, 4H), 7.31-7.26(m, 4H), 6.09 (d, J=2.1 Hz, 4H), 4.36 (q, J=7.1 Hz, 4H), 3.67-3.62 (m,4H), 3.49-3.42 (m, 4H), 3.31 (d, J=1.9, 6H), 1.38 (t, J=7.1 Hz, 6H).

Step C:1-[6-chloro-5-mercapto-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a stirred cooled (0° C.) solution of1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-(2-nitro-phenyldisulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (2.99 g, 5.29 mmol) and EtOH (24 mL) was added dropwisea solution of NaBH₄ (0.729 g, 19.3 mmol), EtOH (24 mL), and water (10mL) over 10 minutes. The reaction mixture was stirred for 15 min andadditional NaBH₄ (0.486 g, 12.8 mmol) in EtOH (16 mL) and water (6.7 mL)was added. The reaction mixture was stirred for an additional 30 min andthen partitioned between DCM (200 mL) and water (200 mL). The aqueouslayer was acidified to pH 5 with 1M HCl and the product was extractedwith DCM (3×300 mL). The organic layers were combined, dried, filtered,and concentrated under reduced pressure. The residue was purified (FCC)(5-80% EtOAc/hexanes) to yield the titled compound (1.27 g, 48%) as a2:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C₁₇H₁₉ClN₄O₄S,410.1; m/z found, 411.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 8.85-8.84 (m,2H), 8.17 (s, 2H), 7.75 (s, 0.67H), 7.72 (s, 1.33H), 7.68 (s, 1.33H),7.64 (s, 0.67H), 6.10-6.09 (m, 4H), 4.36 (q, J=7.1 Hz, 4H), 4.02 (s,0.67H), 3.93 (s, 1.33H), 3.66-3.62 (m, 4H), 3.47-3.44 (m, 4H), 3.31-3.30(m, 6H), 1.38 (t, J=7.1 Hz, 6H). Large-scale synthesis of the titledcompound also provided a dimer by-product, where the dimer linkage isthru the sulfur bond forming a disulfide intermediate of1-[6-chloro-5-mercapto-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester, this by-product was isolated but not tested: MS(ESI/CI): mass calcd. for C₃₄H₃₆Cl₂N₈O₈S₂, 818.1; m/z found, 819.1[M+H]⁺.

Step D:1-[5-benzylsulfanyl-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a solution of1-[6-chloro-5-mercapto-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.300 g, 0.730 mmol), benzyl bromide (0.130 mL, 1.10mmol) and DMF (20 mL) was added potassium carbonate (0.151 g, 1.10mmol). The reaction mixture was stirred for 15 min at 23° C. and pouredonto water (40 mL). The product was extracted with EtOAc (3×50 mL). Theorganic layers were combined, dried, filtered, and concentrated underreduced pressure. The residue was purified (FCC) (2-50% EtOAc/hexanes)to yield the titled compound (0.330 g, 90%). MS (ESI/CI): mass calcd.for C₂₄H₂₅ClN₄O₄S, 500.1; m/z found, 501.1 [M+H]⁺.

Step E:1-(5-benzylsulfanyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester. To a mixture of1-[5-benzylsulfanyl-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (160 mg, 0.319 mmol) and EtOH (3.2 mL) was added 4M HClin dioxane (3.21 mL, 12.8 mmol). The mixture stirred for 18 h at 23° C.The reaction mixture was concentrated and the resulting residue wastriturated in Et₂O. The suspension was filtered and washed with Et₂O toyield the titled compound (0.125 g, 95%) MS (ESI/CI): mass calcd. forC₂₀H₁₇ClN₄O₂S, 412.1; m/z found, 413.1 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆); 13.53 (d, J=12.3 Hz, 1H), 8.95 (s, 1H), 8.35 (s, 1H), 7.78 (s,0.5H), 7.65 (s, 0.5H), 7.55 (s, 0.5H), 7.44 (s, 0.5H), 7.38 (d, J=7.2Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 7.25 (s, 1H), 4.32-4.26 (m, 4H), 1.32(t, J=7.1 Hz, 3H).

Step F:1-(5-benzylsulfanyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. To a mixture of1-(5-benzylsulfanyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester (0.115 g, 0.256 mmol), THF (4.8 mL), and water (1.2 mL)was added LiOH.H₂O (0.107 g, 2.56 mmol). The mixture was stirred for 18h at 23° C. The solvent was evaporated, water (3 mL) was added and themixture acidified to pH 3 with 1M HCl. The resulting white precipitatewas filtered and dried to yield the titled compound (97.0 mg, 99%). MS(ESI/CI): mass calcd. for C₁₈H₁₃ClN₄O₂S, 384.0; m/z found, 385.0 [M+H]⁺.¹H NMR (600 MHz, DMSO-d₆): 8.86 (s, 1H), 8.29 (s, 1H), 7.67 (s, 1H),7.53 (s, 1H), 7.39 (d, J=7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 7.25 (t,J=7.1 Hz, 1H), 4.29 (s, 2H).

Example 67:1-[5-(4-tert-Butyl-benzylsulfanyl)-6-chloro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 66,Method A, substituting (4-tert-butyl-phenyl)-methanethiol forphenyl-methanethiol in Step A. MS (ESI/CI): mass calcd. forC₂₂H₂₁ClN₄O₂S, 440.1; m/z found, 441.1 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆): 8.80 (s, 1H), 8.21 (s, 1H), 7.64 (s, 1H), 7.59 (s, 1H),7.34-7.23 (m, 4H), 4.21 (s, 2H), 1.26 (s, 9H).

Example 68:1-[6-Chloro-5-(4-fluoro-benzylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 66,Method A, substituting (4-fluoro-phenyl)-methanethiol forphenyl-methanethiol in Step A. MS (ESI/CI): mass calcd. forC₁₈H₁₂ClFN₄O₂S, 402.0; m/z found, 403.0 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆): 8.85 (s, 1H), 8.28 (s, 1H), 7.67 (s, 1H), 7.60-7.46 (m, 1H),7.39 (dd, J=8.7, 5.5 Hz, 2H), 7.19-7.06 (m, 2H), 4.27 (s, 2H).

Example 69:1-[6-Chloro-5-(2-chloro-benzylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 66,Method A, substituting (2-chloro-phenyl)-methanethiol forphenyl-methanethiol in Step A. MS (ESI/CI): mass calcd. forC₁₈H₁₂Cl₂N₄O₂S, 418.0; m/z found, 419.0 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆): 8.84 (s, 1H), 8.26 (s, 1H), 7.68 (s, 1H), 7.52 (s, 1H), 7.46(dd, J=7.9, 1.2 Hz, 1H), 7.34 (dd, J=7.5, 1.7 Hz, 1H), 7.29 (td, J=7.6,1.8 Hz, 1H), 7.24 (td, J=7.4, 1.3 Hz, 1H), 4.31 (s, 2H).

Example 70:1-(6-Chloro-5-phenethylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 66,Method A, substituting 2-phenyl-ethanethiol for phenyl-methanethiol inStep A. MS (ESI/CI): mass calcd. for C₁₉H₁₅ClN₄O₂S, 398.1; m/z found,399.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 13.26 (s, 1H), 8.86 (s, 1H),8.28 (s, 1H), 7.69 (s, 1H), 7.60 (s, 1H), 7.34-7.29 (m, 4H), 7.24-7.21(m, 1H), 3.30-3.25 (m, 2H), 2.95-2.90 (m, 2H).

Example 71:1-(6-Methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: 5-Methylsulfanyl-2-nitro-4-trifluoromethyl-phenylamine. To asolution of 5-chloro-2-nitro-4-trifluoromethyl-phenylamine (2.02 g, 8.40mmol) and DMF (40 mL) was added sodium thiomethoxide (0.618 g, 8.82mmol). The mixture was heated to 90° C. for 50 min, then poured intobrine. Water was added to bring the total volume to 300 mL and theorange precipitate was collected to yield the titled compound (2.02 g,95%). ¹H NMR (400 MHz, CDCl₃): 8.42 (s, 1H), 6.51 (s, 1H), 6.39 (br s,2H), 2.53 (s, 3H).

Step B:1-[1-(2-Methoxy-ethoxymethyl)-6-methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. The titled compound was prepared in a manner analogousto EXAMPLE 27, Steps A-E, substituting5-methylsulfanyl-2-nitro-4-trifluoromethyl-phenylamine for3-chloro-2-nitro-phenylamine in Step A. The resulting product wasrecovered as a 1:1 mixture of regioisomers. MS (ESI/CI): mass calcd. forC₁₉H₂₁F₃N₄O₄S, 458.1; m/z found, 459.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.91 (s, 1H), 8.88 (s, 1H), 8.21-8.19 (m, 2H), 8.03 (s, 1H), 7.96 (s,1H), 7.76 (s, 1H), 7.65 (s, 1H), 6.22-6.19 (m, 4H), 4.37 (q, J=7.1 Hz,4H), 3.70-3.63 (m, 4H), 3.49-3.45 (m, 4H), 3.32-3.30 (m, 6H), 2.61-2.57(m, 6H), 1.39 (t, J=7.1 Hz, 6H).

Step C:1-(6-Methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. To a stirred solution of1-[1-(2-methoxy-ethoxymethyl)-6-methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.200 g, 0.436 mmol) and acetic acid (1.3 mL) wasadded 6M aq. hydrochloric acid (1.3 mL). The reaction mixture was heatedto 100° C. for 18 h and then cooled to 23° C. The precipitate wascollected to yield the titled compound as the HCl salt (0.118 g, 71%yield). MS (ESI/CI): mass calcd. for C₁₃H₉F₃N₄O₂S, 342.0; m/z found,343.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.92 (d, J=0.6 Hz, 1H), 8.33(d, J=0.4 Hz, 1H), 7.90 (s, 1H), 7.68 (s, 1H), 2.59 (s, 3H).

Example 72:1-(6-Propylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: 2-Nitro-5-propylsulfanyl-4-trifluoromethyl-phenylamine. To amixture of 5-chloro-2-nitro-4-trifluoromethyl-phenylamine (1.50 g, 6.26mmol), potassium carbonate (1.72 g, 12.5 mmol), and DMF (31 mL) wasadded 1-propanethiol (0.620 mL, 6.86 mmol). The reaction mixture washeated at 90° C. for 16 h, then allowed to cool to 23° C. and pouredinto ice/brine (300 mL). The resulting yellow precipitate was collectedto yield the titled compound (1.67 g, 95%). MS (ESI/CI): mass calcd. forC₁₀H₁₁F₃N₂O₂S, 280.1; m/z found, 281.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.41 (s, 1H), 6.58 (s, 1H), 6.36 (br s, 2H), 2.97 (t, J=7.3 Hz, 2H),1.87-1.72 (m, 2H), 1.10 (t, J=7.4 Hz, 3H).

Step B:1-(6-Propylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE71, Steps B-C. The residue was purified by reverse-phase HPLC to yieldthe titled compound. MS (ESI/CI): mass calcd. for C₁₅H₁₃F₃N₄O₂S, 370.1;m/z found, 371.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomericbroadening): 13.77 (s, 1H), 13.02 (s, 1H), 8.92 (d, J=0.6 Hz, 1H), 8.34(d, J=0.6 Hz, 1H), 8.17-7.54 (m, 2H), 3.02 (t, J=7.1 Hz, 2H), 1.68-1.52(m, 2H), 0.98 (t, J=7.3 Hz, 3H).

Example 73:1-(6-Isopropylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 72,substituting 2-propanethiol for 1-propanethiol in Step A. MS (ESI/CI):mass calcd. for C₁₅H₁₃F₃N₄O₂S, 370.1; m/z found, 371.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD, tautomeric broadening): 8.94 (s, 1H), 8.21 (s, 1H),8.03-7.78 (m, 2H), 3.53-3.38 (m, 1H), 1.29 (d, J=6.7 Hz, 6H).

Example 74:1-(5-Fluoro-6-methylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 71,substituting 4,5-difluoro-2-nitro-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₂H₉FN₄O₂S, 292.0; m/z found, 293.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): 8.87 (s, 1H), 8.29 (s, 1H), 7.48 (d, J=6.7 Hz, 1H), 7.43(d, J=10.1 Hz, 1H), 2.52 (s, 3H).

Example 75:1-(5-Chloro-6-methylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 71,substituting 4,5-dichloro-2-nitro-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₃H₂ClN₄O₂S, 308.0; m/z found, 309.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆): 8.87 (d, J=0.6 Hz, 1H), 8.30 (d, J=0.5 Hz, 1H), 7.67(s, 1H), 7.43 (s, 1H), 2.54 (s, 3H).

Example 76:1-(5-Chloro-6-ethylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 71,substituting 4,5-dichloro-2-nitro-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine and sodium thioethoxidefor sodium thiomethoxide in Step A. MS (ESI/CI): mass calcd. forC₁₃H₁₁ClN₄O₂S, 322.0; m/z found, 323.0 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆): 8.85 (s, 1H), 8.27 (s, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 2.99(q, J=7.3 Hz, 2H), 1.25 (t, J=7.3 Hz, 3H).

Example 77:1-(5-Chloro-6-isopropylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 71,substituting 4,5-dichloro-2-nitro-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine and sodiumthioisopropoxide for sodium thiomethoxide in Step A. MS (ESI/CI): masscalcd. for C₁₄H₁₃ClN₄O₂S, 336.0; m/z found, 337.0 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 8.89 (s, 1H), 8.30 (s, 1H), 7.70 (s, 1H), 7.68 (s, 1H),3.56-3.48 (m, 1H), 1.27 (d, J=6.6 Hz, 6H).

Example 78:1-(5-Chloro-6-propylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 72,substituting 4,5-dichloro-2-nitro-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A; andprecipitating the final compound in Step B without purification byreverse-phase HPLC. MS (ESI/CI): mass calcd. for C₁₄H₁₃ClN₄O₂S, 336.0;m/z found, 337.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.88 (s, 1H), 8.30(s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 2.98 (t, J=7.2 Hz, 2H), 1.64 (h,J=7.3 Hz, 2H), 1.02 (t, J=7.3 Hz, 3H).

Example 79:1-(6-Methylsulfanyl-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 71,substituting 5-chloro-2-nitro-4-trifluoromethoxy-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₃H₉F₃N₄O₃S, 358.0; m/z found, 359.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, tautomeric broadening): 13.00 (br s, 1H), 8.88 (s,1H), 8.32 (s, 1H), 7.81-7.12 (m, 2H), 2.54 (s, 3H).

Example 80:1-(6-Isopropylsulfanyl-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 72,substituting 5-chloro-2-nitro-4-trifluoromethoxy-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine and 2-propanethiol for1-propanethiol in Step A. MS (ESI/CI): mass calcd. for C₁₅H₁₃F₃N₄O₃S,386.1; m/z found, 387.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomericbroadening): 13.65 (s, 1H), 13.00 (s, 1H), 8.89 (d, J=0.5 Hz, 1H), 8.32(d, J=0.5 Hz, 1H), 7.65 (br s, 2H), 3.57-3.44 (br m, 1H), 1.24 (d, J=6.6Hz, 6H).

Example 81:1-(6-Propylsulfanyl-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 72,substituting 5-chloro-2-nitro-4-trifluoromethoxy-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₅H₁₃F₃N₄O₃S, 386.1; m/z found, 387.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, tautomeric broadening): 13.80-12.75 (m, 2H), 8.88 (d,J=0.6 Hz, 1H), 8.32 (d, J=0.6 Hz, 1H), 7.57 (s, 2H), 2.98 (t, J=7.2 Hz,2H), 1.68-1.53 (m, 2H), 0.99 (t, J=7.3 Hz, 3H).

Example 82:1-[6-Chloro-5-(toluene-3-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

Step A:1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-(toluene-3-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a solution of1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from EXAMPLE 60, product from Step F)(0.160 g, 0.319 mmol) and MeOH (1.6 mL) was added a solution of Oxone®(0.412 g, 0.671 mmol) and water (1.7 mL) at 23° C. The reaction mixturewas stirred at 23° C. for 16 h. Dichloromethane (30 mL) was addedfollowed by a solution of sodium thiosulfate (0.106 g, 0.670 mmol) in80% saturated aq. NaHCO₃ (30 mL). The mixture was stirred vigorouslyuntil both layers were clear. The organic layer was collected and thewater layer extracted with CH₂Cl₂ (2×50 mL). The organic layers werecombined, dried, filtered, and concentrated under reduced pressure. Theresidue was purified (FCC) (0-100% EtOAc/hexanes) to yield the titledcompound (0.105 mg, 62%) as a mixture of regioisomers. MS (ESI/CI): masscalcd. for C₂₄H₂₅ClN₄O₆S, 532.1; m/z found, 533.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 8.90 (d, J=0.6 Hz, 1.5H), 8.89 (d, J=0.6 Hz, 0.5H), 8.73(br s, 1.5H), 8.69 (br s, 0.5H), 8.19 (d, J=0.6 Hz, 0.5H), 8.18 (d,J=0.6, 1.5H), 7.79-7.75 (m, 2H), 7.75-7.72 (m, 2H), 7.71 (s, 0.5H), 7.67(s, 1.5H), 7.39-7.36 (m, 4H), 6.27 (s, 1H), 6.14 (s, 3H), 4.40-4.32 (m,4H), 3.71-3.67 (m, 1H), 3.66-3.61 (m, 3H), 3.49-3.45 (m, 1H), 3.44-3.39(m, 3H), 3.28 (s, 1.5H), 3.24 (s, 4.5H), 2.38 (br s, 6H), 1.38-1.33 (m,6H).

Step B:1-[6-Chloro-5-(toluene-3-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE60, steps G-H. MS (ESI/CI): mass calcd. for C₁₈H₁₃ClN₄O₄S, 416.0; m/zfound, 417.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.93 (d, J=0.5 Hz, 1H),8.44 (s, 1H), 8.33 (d, J=0.4 Hz, 1H), 7.75-7.69 (m, 3H), 7.53-7.48 (m,2H), 2.37 (s, 3H).

Example 83:1-(5-Benzenesulfonyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 82,from1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-phenylsulfanyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 62). MS (ESI/CI): masscalcd. for C₁₇H₁₁ClN₄O₄S, 402.0; m/z found, 403.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): 8.94 (s, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 7.95-7.89 (m,2H), 7.76 (br s, 1H), 7.74-7.67 (m, 1H), 7.65-7.58 (m, 2H).

Example 84:1-[6-Chloro-5-(4-methoxy-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 82from1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-(4-methoxy-phenylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 65). MS (ESI/CI): masscalcd. for C₁₈H₁₃ClN₄O₅S, 432.0; m/z found, 433.0 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 14.09 (br s, 1H), 13.04 (br s, 1H), 8.94 (s, 1H), 8.42(s, 1H), 8.35 (s, 1H), 7.89-7.84 (m, 2H), 7.75 (brs, 1H), 7.14-7.10 (m,2H), 3.84 (s, 3H).

Example 85:1-[6-Chloro-5-(4-chloro-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

Step A:1-[6-Chloro-5-(4-chloro-benzenesulfonyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a solution of1-[6-chloro-5-(4-chloro-phenylsulfanyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 61) (2.69 g, 5.16 mmol) anddichloromethane (26 mL) was added mCPBA (2.43 g, 10.8 mmol) at 23° C.The reaction was stirred for 16 h at 23° C. Dichloromethane (30 mL) wasadded followed by a solution of sodium thiosulfate (1.71 g, 10.8 mmol)in 80% saturated aqueous NaHCO₃ (30 mL). The mixture was stirredvigorously until both layers were clear. The organic layer was collectedand the aqueous layer extracted with CH₂Cl₂ (2×80 mL). The organiclayers were combined, dried, filtered, and concentrated under reducedpressure. The residue was purified (FCC) (0-100% EtOAc/hexanes) to yieldthe titled compound (2.55 g, 89%) as a mixture of regioisomers. MS(ESI/CI): mass calcd. for C₂₃H₂₂Cl₂N₄O₆S, 552.1; m/z found, 553.1[M+H]f. ¹H NMR (400 MHz, CDCl₃): 8.91-8.89 (m, 2H), 8.73 (s, 1.4H), 8.68(s, 0.6H), 8.20 (d, J=0.6 Hz, 0.6H), 8.18 (d, J=0.6 Hz, 1.4H), 7.91-7.87(m, 4H), 7.72 (s, 0.6H), 7.68 (s, 1.4H), 7.48-7.43 (m, 4H), 6.27 (s,1.2H), 6.15 (s, 2.8H), 4.39-4.32 (m, 4H), 3.71-3.66 (m, 1.2H), 3.67-3.62(m, 2.8H), 3.48-3.45 (m, 1.2H), 3.44-3.40 (m, 2.8H), 3.28 (s, 1.8H),3.24 (s, 4.2H), 1.40-1.34 (m, 6H).

Step B:1-[6-chloro-5-(4-chloro-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a mixture of1-[6-chloro-5-(4-chloro-benzenesulfonyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (2.55 g, 4.61 mmol) and EtOH (11.5 mL) was added 4M HClin dioxane (11.5 mL). The mixture was stirred for 3 h at 23° C. Thereaction mixture was concentrated and Et₂O was added. The solids werefiltered and washed with Et₂O to yield the titled compound (1.92 g,89%). MS (ESI/CI): mass calcd. for C₁₉H₁₄Cl₂N₄O₄S, 464.0; m/z found,465.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 9.02 (s, 1H), 8.45 (s, 1H),8.40 (s, 1H), 7.95-7.92 (m, 2H), 7.76 (br s, 1H), 7.70-7.67 (m, 2H),4.30 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).

Step C:1-[6-chloro-5-(4-chloro-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid. To a mixture of1-[6-chloro-5-(4-chloro-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (1.92 g, 4.13 mmol), THF (16 mL), and water (5 mL) wasadded LiOH.H₂O (0.693 g, 16.5 mmol). The mixture was stirred for 18 h at23° C. The solvent was evaporated, water (10 mL) was added and themixture acidified with 1M HCl. The resulting precipitate was filteredand dried to yield the titled compound (1.73 g, 94%). MS (ESI/CI): masscalcd. for C₁₇H₁₀Cl₂N₄O₄S, 436.0; m/z found, 437.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆): 8.89 (s, 1H), 8.40 (s, 1H), 8.25 (s, 1H), 7.93-7.90 (m,2H), 7.69-7.66 (m, 3H).

Example 86:1-[6-Chloro-5-(4-trifluoromethoxy-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

Step A:1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-(4-trifluoromethoxy-phenylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. The titled compound was prepared in a manner analogousto Example 60, steps A-F, substituting 4-trifluoromethoxy-benzenethiolfor 3-methyl-benzenethiol in Step A.

Step B:1-[6-Chloro-5-(4-trifluoromethoxy-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in manner analogous to Example85. MS (ESI/CI): mass calcd. for C₁₈H₁₀ClF₃N₄O₅S, 486.0; m/z found,487.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.77 (s, 1H), 8.29 (s, 1H),8.02 (s, 1H), 8.01-7.97 (m, 2H), 7.56 (d, J=8.1 Hz, 2H), 7.45 (s, 1H).

Example 87:1-[6-Chloro-5-(3,4-dichloro-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[6-chloro-5-(3,4-dichloro-phenylsulfanyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 63). MS (CI): mass calcd.for C₁₇H₉Cl₃N₄O₄S, 469.9; m/z found, 468.9 [M−H]⁻. ¹H NMR (600 MHz,DMSO-d₆): 8.95 (s, 1H), 8.48 (br s, 1H), 8.34 (s, 1H), 8.16 (d, J=1.6Hz, 1H), 7.92-7.88 (m, 2H), 7.78 (br s, 1H).

Example 88:1-[6-Chloro-5-(3-methoxy-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-(3-methoxy-phenylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 64). MS (ESI/CI): masscalcd. for C₁₈H₁₃ClN₄O₅S, 432.0; m/z found, 433.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): 14.15 (s, 1H), 13.04 (s, 1H), 8.95 (d, J=0.5 Hz, 1H),8.45 (s, 1H), 8.36 (s, 1H), 7.77 (br s, 1H), 7.53 (t, J=8.0 Hz, 1H),7.48-7.43 (m, 1H), 7.41-7.38 (m, 1H), 7.27 (ddd, J=8.3, 2.6, 1.0 Hz,1H), 3.81 (s, 3H).

Example 89:1-(6-Chloro-5-phenylmethanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[5-benzylsulfanyl-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 66). MS (ESI/CI): masscalcd. for C₁₈H₁₃ClN₄O₄S, 416.0; m/z found, 417.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): 8.92 (s, 1H), 8.33 (s, 1H), 7.98-7.82 (m, 2H), 7.33-7.15(m, 5H), 4.86 (s, 2H).

Example 90:1-[6-Chloro-5-(2,4,6-trimethyl-phenylmethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

Step A:1-[6-Chloro-1-(2-methoxy-ethoxymethyl)-5-(2,4,6-trimethyl-benzylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. The titled compound was prepared in a manner analogousto Example 66, Method A, steps A-B, substituting(2,4,6-trimethyl-phenyl)-methanethiol for phenyl-methanethiol in Step A.MS (ESI/CI): mass calcd. for C₂₇H₃₁ClN₄O₄S, 542.2; m/z found, 543.2[M+H]⁺.

Step B:1-[6-Chloro-5-(2,4,6-trimethyl-phenylmethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in manner analogous to Example85. MS (ESI/CI): mass calcd. for C₂₁H₁₉ClN₄O₄S, 458.1; m/z found, 459.1[M+H]f. ¹H NMR (600 MHz, DMSO-d₆): 8.95 (s, 1H), 8.35 (s, 1H), 8.13 (s,1H), 7.94 (s, 1H), 6.90 (s, 2H), 4.85 (s, 2H), 2.32 (s, 6H), 2.23 (s,3H).

Example 91:1-[6-Chloro-5-(4-methoxy-phenylmethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

Step A:1-[6-Chloro-5-(4-methoxy-benzylsulfanyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. The titled compound was prepared in a manner analogousto Example 66, Method A, steps A-B, substituting(4-methoxy-phenyl)-methanethiol for phenyl-methanethiol in Step A. MS(ESI/CI): mass calcd. for C₂₅H₂₇ClN₄O₅S, 530.1; m/z found, 531.1 [M+H]⁺.

Step B:1-[6-Chloro-5-(4-methoxy-phenylmethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in manner analogous to Example85. MS (ESI/CI): mass calcd. for C₁₉H₁₅ClN₄O₅S, 446.1; m/z found, 447.0[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.92 (s, 1H), 8.34 (s, 1H), 8.03 (s,0.6H), 7.92 (s, 0.4H), 7.83 (s, 0.6H), 7.74 (s, 0.4H), 7.11 (d, J=8.7Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 4.79 (s, 2H), 3.68 (s, 3H).

Example 92:1-[6-Chloro-5-(4-fluoro-phenylmethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[6-chloro-5-(4-fluoro-benzylsulfanyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 68. MS (ESI/CI): mass calcd.for C₁₈H₁₂ClFN₄O₄S, 434.0; m/z found, 435.0 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆): 8.92 (s, 1H), 8.32 (s, 1H), 7.95-7.83 (m, 2H), 7.26-7.21 (m,2H), 7.11 (t, J=8.8 Hz, 2H), 4.87 (s, 2H).

Example 93:1-[6-Chloro-5-(2-chloro-phenylmethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[6-chloro-5-(2-chloro-benzylsulfanyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 69). MS (ESI/CI): masscalcd. for C₁₈H₁₂Cl₂N₄O₄S, 450.0; m/z found, 451.0 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 14.05 (s, 1H), 13.02 (s, 1H), 8.94 (s, 1H), 8.34 (s, 1H),8.04-7.83 (m, 2H), 7.43 (dd, J=7.2 Hz, 2.1 Hz, 1H), 7.40 (dd, J=7.7 Hz,1.5, 1H), 7.34 (pd, J=7.3 Hz, 1.8 Hz, 2H), 5.02 (s, 2H).

Example 94:1-[6-Chloro-5-(2-phenyl-ethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-phenethylsulfanyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 70). MS (ESI/CI): masscalcd. for C₁₉H₁₅ClN₄O₄S, 430.1; m/z found, 431.0 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 8.95 (s, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 7.84 (s, 1H),7.22-7.16 (m, 4H), 7.15-7.11 (m, 1H), 3.88-3.82 (m, 2H), 2.96-2.87 (m,2H).

Example 95:1-(5-Chloro-6-ethanesulfinyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A:1-[1-(2-Methoxy-ethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. The titled compound was prepared in a manner analogousto EXAMPLE 71, Steps A-B, substituting 4,5-dichloro-2-nitro-phenylaminefor 5-chloro-2-nitro-4-trifluoromethyl-phenylamine and sodiumthioethoxide for sodium thiomethoxide in Step A. A 1:1 mixture ofregioisomers was observed. ¹H NMR (600 MHz, CDCl₃): 8.86 (d, J=0.6 Hz,1H), 8.85 (d, J=0.6 Hz, 1H), 8.18 (s, 2H), 7.75 (s, 1H), 7.68 (s, 1H),7.67 (s, 1H), 7.56 (s, 1H), 6.14 (s, 2H), 6.10 (s, 2H), 4.36 (q, J=7.1Hz, 4H), 3.68-3.63 (m, 4H), 3.48-3.44 (m, 4H), 3.31 (s, 3H), 3.31 (s,3H), 3.02 (p, J=7.3 Hz, 4H), 1.41-1.36 (m, 12H).

Step B:1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfinyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a mixture of1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.501 g, 1.14 mmol) and MeOH (5.7 mL) was added asolution of Oxone®/potassium peroxymonosulfate (1.47 g, 2.40 mmol) inwater (5.7 mL). The mixture was stirred for 44 h at 23° C. EtOAc (50 mL)and water (30 mL) were added and the biphasic mixture stirred. Thelayers were separated and the aqueous layer was further extracted withEtOAc (50 mL). The combined organic layers were washed with brine,dried, filtered, and concentrated under reduced pressure. The residuewas purified (FCC) (10-80% EtOAc/hex) to yield the titled compound(0.232 g, 45% yield, 2:1 mixture of regioisomers) and1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.260 g, 48% yield, 5:2 mixture of regioisomers). MS(ESI/CI): mass calcd. for C₁₃H₂₃ClN₄O₅S, 454.1; m/z found, 455.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.90 (d, J=0.6 Hz, 1H), 8.20 (d, J=0.6 Hz, 1H),8.13 (s, 1H), 7.74 (s, 1H), 6.25-6.16 (m, 2H), 4.37 (q, J=7.1 Hz, 2H),3.68-3.62 (m, 2H), 3.46-3.41 (m, 2H), 3.27 (s, 3H), 3.26-3.13 (m, 1H),2.94-2.83 (m, 1H), 1.39 (t, J=7.1 Hz, 3H), 1.27 (t, J=7.4 Hz, 3H).

Step C:1-(5-Chloro-6-ethanesulfinyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester. To a solution of1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfinyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.191 g, 0.420 mmol) in ethanol (2 mL) was added 4MHCl in dioxane (2 mL). The reaction mixture was stirred at 23° C. for 2h. The resulting precipitate was collected and rinsed with diethyl etherto yield the titled compound (0.103 g, 67% yield). MS (ESI/CI): masscalcd. for C₁₅H₁₅ClN₄O₃S, 366.1; m/z found, 367.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): 9.02 (d, J=0.6 Hz, 1H), 8.40 (d, J=0.6 Hz, 1H), 7.87 (s,1H), 7.80 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 3.17 (dq, J=14.6, 7.3 Hz,1H), 2.84 (dq, J=14.6, 7.4 Hz, 1H), 1.32 (t, J=7.1 Hz, 3H), 1.08 (t,J=7.3 Hz, 3H).

Step D:1-(5-Chloro-6-ethanesulfinyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. To a solution of1-(5-chloro-6-ethanesulfinyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester (100 mg, 0.273 mmol), THF (1.0 mL), and water (0.33 mL)was added lithium hydroxide (31.3 mg, 0.818 mmol). The mixture wassonicated briefly, and stirred at 23° C. for 56 h. The solvent wasevaporated, water was added, and the resulting solution was acidified topH 1 with 1M aq. HCl. The precipitate was collected to yield the titledcompound (79.1 mg, 85% yield). MS (ESI/CI): mass calcd. forC₁₃H₁₁ClN₄O₃S, 338.0; m/z found, 339.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆,tautomeric broadening): 13.88 (br s, 1H), 13.01 (brs, 1H), 8.94 (s, 1H),8.40 (s, 1H), 8.03-7.55 (m, 2H), 3.23-3.11 (m, 1H), 2.89-2.78 (m, 1H),1.08 (t, J=7.4 Hz, 3H).

Example 96:1-(5-Chloro-6-ethanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A:1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a mixture of1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (EXAMPLE 95, product from Step A) (0.501 g, 1.14 mmol)and methanol (5.7 mL) was added a solution of Oxone®/potassiumperoxymonosulfate (1.47 g, 2.40 mmol) in water (5.7 mL). The mixture wasstirred for 44 h at 23° C. EtOAc (50 mL) and water (30 mL) were addedand the biphasic mixture was stirred. The layers were separated and theaqueous layer was further extracted with EtOAc (50 mL). The combinedorganic layers were washed with brine, dried, filtered, and concentratedunder reduced pressure. The residue was purified (FCC) (10-80%EtOAc/hexanes) to yield the titled compound (0.260 g, 48% yield, 5:2mixture of regioisomers) and1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfinyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.232 g, 45% yield, 2:1 mixture of regioisomers). MS(ESI/CI): mass calcd. for C₁₃H₂₃ClN₄O₆S, 470.1; m/z found, 471.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.91 (d, J=0.6 Hz, 1H), 8.53 (s, 1H), 8.20 (d,J=0.6 Hz, 1H), 7.82 (s, 1H), 6.21 (s, 2H), 4.37 (q, J=7.1 Hz, 2H),3.72-3.67 (m, 2H), 3.53-3.42 (m, 4H), 3.29 (s, 3H), 1.39 (t, J=7.1 Hz,3H), 1.30 (t, J=7.4 Hz, 3H).

Step B:1-(5-Chloro-6-ethanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE95, Steps C-D from1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. MS (ESI/CI): mass calcd. for C₁₃H₁₁ClN₄O₄S, 354.0; m/zfound, 355.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomeric broadening):13.02 (br s, 1H), 8.95 (d, J=0.6 Hz, 1H), 8.36 (d, J=0.5 Hz, 1H), 8.18(s, 1H), 7.90 (br s, 1H), 3.53 (q, J=7.4 Hz, 2H), 1.14 (t, J=7.4 Hz,3H).

Example 97:1-(6-Methanesulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 95,substituting 5-chloro-2-nitro-4-trifluoromethyl-phenylamine for4,5-dichloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₃H₉F₃N₄O₄S, 374.0; m/z found, 375.0 [M+H]f. ¹H NMR (400 MHz, DMSO-de,tautomeric broadening): 14.41 (brs, 1H), 13.08 (br s, 1H), 8.99 (s, 1H),8.60-7.85 (m, 3H), 3.33 (s, 3H).

Example 98:1-(5-Fluoro-6-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to Example 95,substituting 4,5-difluoro-2-nitro-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₂H₉FN₄O₄S, 324.0; m/z found, 325.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆, tautomeric broadening): 14.03 (br s, 1H), 13.04 (br s,1H), 8.95 (d, J=0.4 Hz, 1H), 8.36 (s, 1H), 8.15-7.41 (m, 2H), 3.35 (s,3H).

Example 99:1-(5-Chloro-6-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to Example 95,substituting 4,5-dichloro-2-nitro-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₂H₉ClN₄O₄S, 340.0; m/z found, 341.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-de, tautomeric broadening): 14.10 (br s, 1H), 13.05 (brs, 1H), 8.96 (s, 1H), 8.37 (s, 1H), 8.32-7.63 (m, 2H), 3.40 (s, 3H).

Example 100:1-(6-Methanesulfonyl-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to Example 95,substituting 5-chloro-2-nitro-4-trifluoromethoxy-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₃H₉F₃N₄O₅S, 390.0; m/z found, 391.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, tautomeric broadening): 14.19 (br s, 1H), 13.07 (brs, 1H), 8.95 (s, 1H), 8.38 (s, 1H), 8.11 (br s, 1H), 7.81 (br s, 1H),3.33 (s, 3H).

Example 101:1-[5-Chloro-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

Step A: 4-chloro-5-isopropylsulfanyl-2-nitro-phenylamine. To a solutionof 4,5-dichloro-2-nitro-phenylamine (3 g, 14.5 mmol) and DMF (73 mL) wasadded sodium thioisopropoxide (4.95 g, 45.6 mmol). The solution washeated to 100° C. for 4 days, cooled, and poured into brine (300 mL).The aqueous layer was extracted with EtOAc (3×200 mL) and the combinedorganic layers were washed with water (3×200 mL) and brine (1×200 mL),dried, filtered, and concentrated under reduced pressure. The crudeproduct was used in the next step without further purification. MS(ESI/CI): mass calcd. for C₉H₁₁ClN₂O₂S, 246.0; m/z found, 247.0 [M+H]⁺.

Step B:1-[5-Chloro-1-(2-methoxy-ethoxymethyl)-6-(propane-2-sulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. The titled compound was prepared in a manner analogousto EXAMPLE 27, Steps A-E, substituting4-chloro-5-isopropylsulfanyl-2-nitro-phenylamine3-chloro-2-nitro-phenylamine in Step A. A 1:1 mixture of regioisomersresulted. MS (ESI/CI): mass calcd. for C₂₀H₂₅ClN₄O₄S, 452.1; m/z found,453.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 8.87-8.86 (m, 2H), 8.18 (d, J=0.4Hz, 2H), 7.81 (s, 1H), 7.77 (s, 1H), 7.72 (s, 1H), 7.70 (s, 1H), 6.14(s, 2H), 6.11 (s, 2H), 4.36 (q, J=7.1 Hz, 4H), 3.69-3.62 (m, 4H),3.55-3.43 (m, 6H), 3.31 (s, 3H), 3.30 (s, 3H), 1.38 (t, J=7.1 Hz, 6H),1.35 (dd, J=6.7, 2.0 Hz, 12H).

Step C:1-[5-Chloro-1-(2-methoxy-ethoxymethyl)-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a solution of1-[5-chloro-1-(2-methoxy-ethoxymethyl)-6-(propane-2-sulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.249 g, 0.550 mmol) and dichloromethane (2.8 mL) wasadded m-CPBA (0.259 g, 1.15 mmol, 77% w/w). The reaction mixture stirredfor 2.5 days at 23° C. Ethyl acetate (20 mL) and a solution of sodiumthiosulfate (0.182 g, 1.15 mmol) in 80% saturated aqueous sodiumcarbonate (10 mL) were added and the layers were stirred vigorously for10 minutes, until clear. The layers were separated and the aqueous layerwas extracted with EtOAc (2×30 mL). The combined organic layers werewashed with brine (10 mL), dried, and concentrated under reducedpressure. The residue was purified (FCC) (10-60% EtOAc/hexanes) to yieldthe titled compound (0.254 g, 95% yield) as a 10:9 mixture ofregioisomers. MS (ESI/CI): mass calcd. for C₂₀H₂₅ClN₄O₆S, 484.1; m/zfound, 485.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 8.91 (d, J=0.5 Hz, 1H),8.51 (s, 1H), 8.20 (d, J=0.5 Hz, 1H), 7.81 (s, 1H), 6.21 (s, 2H), 4.37(q, J=7.1 Hz, 2H), 3.90-3.83 (m, 1H), 3.72-3.68 (m, 2H), 3.49-3.45 (m,2H), 3.29 (s, 3H), 1.39 (t, J=7.1 Hz, 3H), 1.35 (d, J=6.8 Hz, 6H).

Step D:1-[5-Chloro-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a solution of1-[5-chloro-1-(2-methoxy-ethoxymethyl)-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.243 g, 0.501 mmol) in ethanol (1.8 mL) was added 4MHCl in dioxane (1.8 mL). The reaction mixture was stirred at 23° C. for1.5 h. Diethyl ether was added and the precipitate collected to yieldthe titled compound (0.183 g, 92% yield). MS (ESI/CI): mass calcd. forC₁₆H₁₇ClN₄O₄S, 369.1; m/z found, 397.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO):9.03 (d, J=0.6 Hz, 1H), 8.42 (d, J=0.6 Hz, 1H), 8.16 (s, 1H), 7.90 (s,1H), 4.31 (q, J=7.1 Hz, 2H), 3.89-3.76 (m, 1H), 1.33 (t, J=7.1 Hz, 3H),1.21 (d, J=6.8 Hz, 6H).

Step E:1-[5-Chloro-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid. To a solution of1-[5-chloro-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.179 mg, 0.451 mmol), THF (1.7 mL), and water (0.55mL) was added LiOH.H₂O (56.8 mg, 1.35 mmol). The mixture was sonicatedbriefly, and stirred at 23° C. for 56 h. The solvent was evaporated,water was added, and the resulting solution was acidified to pH 1 with1M aq. HCl. The precipitate was collected to yield the titled compound(0.146 g, 86% yield). MS (ESI/CI): mass calcd. for C₁₄H₁₃ClN₄O₄S, 368.0;m/z found, 369.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-de, tautomericbroadening): 14.07 (s, 1H), 13.03 (s, 1H), 8.95 (d, J=0.4 Hz, 1H), 8.36(s, 1H), 8.16 (s, 1H), 8.09-7.64 (m, 1H), 3.88-3.76 (m, 1H), 1.22 (d,J=7.9 Hz, 6H).

Example 102:1-[5-Chloro-6-(propane-1-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

Step A: 4-Chloro-2-nitro-5-propylsulfanyl-phenylamine. To a mixture of4,5-dichloro-2-nitro-phenylamine (3.50 g, 16.9 mmol), potassiumcarbonate (4.67 g, 33.8 mmol), and DMF (85 mL) was added 1-propanethiol(2.30 mL, 25.4 mmol). The reaction mixture was heated at 90° C. for 1.5h, and allowed to cool to 23° C. The mixture was poured into ice/brine(600 mL) and the resulting precipitate was collected to yield the titledcompound (4.09 g, 98%). ¹H NMR (600 MHz, CDCl₃): 8.11 (s, 1H), 6.46 (s,1H), 6.10 (br s, 2H), 2.91 (t, J=7.3 Hz, 2H), 1.85-1.76 (m, 2H), 1.12(t, J=7.4 Hz, 3H).

Step B:1-[5-Chloro-6-(propane-1-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE101, Steps B-E. MS (ESI/CI): mass calcd. for C₁₄H₁₃ClN₄O₄S, 368.0; m/zfound, 369.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆, tautomeric broadening):14.05 (s, 1H), 13.02 (s, 1H), 8.95 (s, 1H), 8.36 (s, 1H), 8.30-8.08 (m,1H), 8.07-7.64 (m, 1H), 3.57-3.44 (m, 2H), 1.64-1.55 (m, 2H), 0.94 (t,J=7.4 Hz, 3H).

Example 103:1-[6-(Propane-2-sulfonyl)-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 102,substituting 5-chloro-2-nitro-4-trifluoromethyl-phenylamine for4,5-dichloro-2-nitro-phenylamine and 2-propanethiol for 1-propanethiolin Step A. MS (ESI/CI): mass calcd. for C₁₅H₁₃F₃N₄O₄S, 402.1; m/z found,403.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomeric broadening):13.68-12.50 (m, 1H), 8.99 (s, 1H), 8.39 (s, 1H), 8.29 (s, 1H), 8.18 (s,1H), 3.59-3.47 (m, 1H), 1.22 (d, J=6.8 Hz, 6H).

Example 104:1-[6-(Propane-1-sulfonyl)-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 102,substituting 5-chloro-2-nitro-4-trifluoromethyl-phenylamine for4,5-dichloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₅H₁₃F₃N₄O₄S, 402.1; m/z found, 403.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆,tautomeric broadening): 14.37 (s, 1H), 13.08 (s, 1H), 8.99 (s, 1H),8.51-7.88 (m, 3H), 3.40-3.32 (m, 2H), 1.75-1.57 (m, 2H), 0.95 (t, J=7.4Hz, 3H).

Example 105:1-[6-(Propane-2-sulfonyl)-5-trifluoromethoxy-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 102,substituting 5-chloro-2-nitro-4-trifluoromethoxy-phenylamine for4,5-dichloro-2-nitro-phenylamine and 2-propanethiol for 1-propanethiolin Step A. MS (ESI/CI): mass calcd. for C₁₅H₁₃F₃N₄O₅S, 418.1; m/z found,419.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomeric broadening): 14.17(s, 1H), 13.07 (s, 1H), 8.95 (s, 1H), 8.40-8.35 (m, 1H), 8.08 (s, 1H),7.78 (s, 1H), 3.59-3.45 (m, 1H), 1.20 (d, J=6.8 Hz, 6H).

Example 106:1-[6-(Propane-1-sulfonyl)-5-trifluoromethoxy-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 102,substituting 5-chloro-2-nitro-4-trifluoromethoxy-phenylamine for4,5-dichloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₅H₁₃F₃N₄O₅S, 418.1; m/z found, 419.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆,tautomeric broadening): 14.17 (s, 1H), 13.06 (s, 1H), 8.95 (s, 1H), 8.37(s, 1H), 8.09 (s, 1H), 7.78 (s, 1H), 3.44-3.34 (m, 2H), 1.67-1.51 (m,2H), 0.93 (t, J=7.4 Hz, 3H).

Example 107:1-(5-Benzenesulfinyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 82,from1-[6-chloro-5-(4-chloro-phenylsulfanyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 61). MS (ESI/CI): masscalcd. for C₁₇H₁₀Cl₂N₄O₃S, 420.0; m/z found, 421.0 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 13.94 (br s, 1H), 13.05 (brs, 1H), 8.93 (s, 1H), 8.34 (s,1H), 8.06 (br s, 1H), 7.78 (br s, 1H), 7.76 (d, J=8.6 Hz, 2H), 7.65-7.58(m, 2H). The enantiomers were separated on a Kromasil® DMB 250×21.2 mm(L×I.D.) preparatory SFC column at 40° C. using 8.5 mL/min of MeOHcontaining 0.2% diisopropyl amine and 34 g/min CO₂, with UV detection at214 nm. The two enantiomers were isolated as the diisopropyl amine salt.MS (ESI/CI): mass calcd. for C₁₇H₁₀Cl₂N₄O₃S, 420.0; m/z found, 421.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 8.56 (s, 1H), 7.85 (s, 1H), 7.71 (s,1H), 7.70-7.66 (m, 2H), 7.60-7.56 (m, 2H), 7.39 (s, 1H), 1.11 (d, J=6.4Hz, 12H).

Example 108:1-(6-Methanesulfinyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A:1-[1-(2-Methoxy-ethoxymethyl)-6-methylsulfinyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a mixture of1-[1-(2-methoxy-ethoxymethyl)-6-methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from EXAMPLE 71, product from Step B)(0.300 g, 0.654 mmol) and methanol (3.3 mL) was added a solution ofOXONE®/potassium peroxymonosulfate (0.402 g, 0.654 mmol) in water (3.3mL). The mixture was allowed to stir for 4 h at 23° C. EtOAc (40 mL) andwater (20 mL) were added and the biphasic mixture was stirred. Thelayers were separated and the aqueous layer was further extracted withEtOAc (30 mL). The combined organic layers were washed with brine (15mL), dried, filtered, and concentrated under reduced pressure. Theresidue was purified (FCC) (20-100% EtOAc/hexanes) to yield the titledcompound (0.249 g, 80% yield) as a 10:9 mixture of regioisomers. MS(ESI/CI): mass calcd. for C₁₉H₂₁F₃N₄O₅S, 474.1; m/z found, 475.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.94 (d, J=0.6 Hz, 1H), 8.58 (s, 1H), 8.22 (s,1H), 8.08 (s, 1H), 6.34-6.23 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 3.74-3.66(m, 2H), 3.51-3.41 (m, 2H), 3.28 (s, 3H), 2.81 (s, 3H), 1.40 (t, J=7.1Hz, 3H).

Step B:1-(6-methanesulfinyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27, Steps F-G. MS (ESI/CI): mass calcd. for C₁₃H₉F₃N₄O₃S, 358.0; m/zfound, 359.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomeric broadening):14.25 (br s, 1H), 13.06 (br s, 1H), 8.98 (s, 1H), 8.38 (d, J=0.5 Hz,1H), 8.34 (br s, 1H), 8.05 (br s, 1H), 2.79 (s, 3H).

The resulting enantiomers were isolated as the respective isopropylaminesalts using preparative chiral SFC. The separation was performed using aChiralpak® AD-H column at 40° C., with a flow rate of 8.6 mL/min ofmethanol with 0.2% isopropylamine and 33 mL/min CO₂, and a columnpressure of 37 bar. Absolute stereochemistry was not assigned for thesecompounds. MS (ESI/CI): mass calcd. for C₁₃H₉F₃N₄O₃S, 358.0; m/z found,359.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.78 (s, 1H), 8.26-7.14 (br s,3H), 8.16 (s, 1H), 8.04 (s, 1H), 7.77 (s, 1H), 3.29 (m, 1H), 2.70 (s,3H), 1.17 (d, J=6.5 Hz, 6H).

Example 109:1-(6-Bromo-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

Step A: 5-Bromo-4-fluoro-2-nitro-phenylamine. A mixture of1-bromo-2,5-difluoro-4-nitro-benzene (1.50 g, 6.30 mmol) and 7M ammoniain methanol (25 mL) was heated in a sealed tube at 60° C. for 15 h. Thereaction mixture was transferred to a round bottom flask, washing thesealed tube with EtOAc. The reaction mixture was concentrated, and thecrude material was used in the next step without further purification.

Step B:1-(6-Bromo-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE60, Steps B-H substituting 5-bromo-4-fluoro-2-nitro-phenylamine for4-chloro-2-nitro-5-m-tolylsulfanyl-phenylamine in Step B and lithiumdiisopropylamide for buthyllithium in Step E. MS (ESI/CI): mass calcd.for C₁₁H₆BrFN₄O₂, 324.0; m/z found, 325.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 12.92 (s, 1H), 8.88 (s, 1H), 8.29 (s, 1H), 7.84 (br s, 1H),7.57 (br s, 1H).

Example 110: 1-(4-Fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 60,Steps B-H substituting 2-fluoro-6-nitro-phenylamine for4-chloro-2-nitro-5-m-tolylsulfanyl-phenylamine in Step B and lithiumdiisopropylamide for buthyllithium in Step E. MS (ESI/CI): mass calcd.for C₁₁H₇FN₄O₂, 246.1; m/z found, 247.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 8.91 (d, J=0.5 Hz, 1H), 8.28 (d, J=0.4 Hz, 1H), 7.35 (d, J=8.0Hz, 1H), 7.22 (td, J=8.1, 4.9 Hz, 1H), 7.06 (dd, J=11.0, 8.1 Hz, 1H).

Example 111:1-(4,5-Difluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 60,Steps D-H substituting 4,5-difluorobenzoimidazole for6-chloro-5-m-tolylsulfanyl-1H-benzoimidazole in Step B and lithiumdiisopropylamide for buthyllithium in Step E. MS (ESI/CI): mass calcd.for C₁₁H₆F₂N₄O₂, 264.1; m/z found, 265.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 13.76 (brs, 1H), 12.97 (brs, 1H), 8.94 (s, 1H), 8.31 (d, J=0.6Hz, 1H), 7.38-7.21 (m, 2H).

Example 112:1-(4,6-Difluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 60,Steps C-H substituting 3,5-difluoro-benzene-1,2-diamine for4-chloro-5-m-tolylsulfanyl-benzene-1,2-diamine in Step C and lithiumdiisopropylamide for buthyllithium in Step E. MS (ESI/CI): mass calcd.for C₁₁H₆F₂N₄O₂, 264.1; m/z found, 265.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 13.84 (brs, 1H), 12.95 (brs, 1H), 8.91 (s, 1H), 8.30 (s, 1H),7.19-7.11 (m, 2H).

Example 113:1-(6-Chloro-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Method A:

The titled compound was prepared in a manner analogous to EXAMPLE 27substituting 5-chloro-2-nitro-4-trifluoromethoxy-phenylamine for3-chloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₂H₆ClF₃N₄O₃, 346.0; m/z found, 347.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 13.37 (s, 1H), 8.88 (s, 1H), 8.29 (s, 1H), 7.80 (s, 1H), 7.71(s, 1H).

Method B:

Step A: 6-Chloro-5-trifluoromethoxy-1H-benzoimidazole. A mixture of5-chloro-2-nitro-4-trifluoromethoxy-phenylamine (2.00 g, 7.80 mmol),sodium dithionite (7.06 g, 40.5 mmol), trimethyl orthoformate (23.1 mL,210 mmol), DMF (23 mL), and acetic acid (4.0 mL) was heated in a sealedtube for 15 h at 100° C. The reaction mixture was cooled to 23° C. andpartitioned between EtOAc (100 mL) and saturated aq. NaHCO₃ (100 mL).The organic layer was collected and the aqueous layer was extracted withEtOAc (2×80 mL). The combined organic layers were dried, filtered, andconcentrated under reduced pressure. The residue was purified (FCC)(0-15% MeOH/DCM) to yield the titled compound (1.46 g, 78%). MS(ESI/CI): mass calcd. for C₈H₄ClF₃N₂O, 236.0; m/z found, 237.0 [M+H]. ¹HNMR (500 MHz, CDCl₃): 8.11 (s, 1H), 7.74 (s, 1H), 7.64 (s, 1H).

Step B:1-(6-Chloro-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE60, Steps D-H. MS (ESI/CI): mass calcd. for C₁₂H₆ClF₃N₄O₂, 346.0; m/zfound, 347.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.90 (s, 1H), 8.32 (s,1H), 7.83 (br s, 1H), 7.74 (br s, 1H).

Method C:

Step A: 4-Chloro-5-trifluoromethoxy-benzene-1,2-diamine.5-Chloro-2-nitro-4-trifluoromethoxy-phenylamine (180 g, 0.7 mol, 1.0equiv.) was dissolved in dry DMF (1 L) and then 5% Pt/C containing 50.2%water (4.0 g) was added. The reaction solution was hydrogenated (50 psi)at room temperature for 16 hours. HPLC analysis indicated completereaction. MS [M+H]⁺ found 225.2. The reaction solution was used on thenext step without isolation.

Step B: 5-Chloro-6-trifluoromethoxy-1,3-dihydro-benzoimidazol-2-one. ThePt/C from Step A was filtered off and washed with dry DMF (250 mL). Thefiltrate solution was concentrated to 750 mL. Activated 3A molecularsieves (100 g) was added and the solution was stirred at roomtemperature for 3 hours. The molecular sieves was filtered off andwashed with dry DMF (250 mL). To the dried DMF solution, was added assolid CDI (125 g, 0.77 mol, 1.1 equiv.), (slightly exothermic), at roomtemperature. After stirring at room temperature for 30 minutes. Water(1.8 L) was added. The resulting suspension was stirred at roomtemperature overnight. The precipitated white solid was collected byfiltration, washed with water, dried thoroughly to afford the titlecompound (154.6 g, 87%). MS [M+H]⁺ found 253.1.

Step C: 2,6-Dichloro-5-trifluoromethoxy-1H-benzoimidazole. Thoroughlydried 5-chloro-6-trifluoromethoxy-1,3-dihydro-benzoimidazol-2-one (154.6g, 0.61 mol, 1.0 equiv.) was suspended in POCl₃ (450 mL, 8.0 equiv.).The reaction solution was heated to reflux temperature for 6 hours andcooled to room temperature. The solution was poured into crushedice/water (˜3 L) slowly with sufficient stirring. The solution wasneutralized to pH=6.0 with NaOH. The precipitated solid was collected byfiltration, washed with water, and dried to afford the title compound(159.97 g, 96%). The crude product was used in the following reactionwithout further purification.

The next 3 steps were performed in a one-pot fashion. The intermediateswere not isolated.

Step D:1-(6-Chloro-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. 2,6-Dichloro-5-trifluoromethoxy-1H-benzoimidazole (160 g, 0.59mol, 1.0 equiv.) was dissolved in dry DMF (1.5 L) and then K₂CO₃ (98 g,0.71 mol, 1.2 equiv.) and dimethylsulfamoyl chloride (85 g, 0.59 mol,1.0 equiv.) were added sequentially. The reaction mixture was stirred atroom temperature for 16 hours to afford2,6-dichloro-5-trifluoromethoxy-benzoimidazole-1-sulfonic aciddimethylamide. Without isolation of2,6-dichloro-5-trifluoromethoxy-benzoimidazole-1-sulfonic aciddimethylamide, 1H-pyrazole-4-carboxylic acid ethyl ester (91 g, 0.65mol, 1.1 equiv.) and K₂CO₃ (98 g, 0.71 mol, 1.2 equiv.) were added tothe reaction mixture. The reaction mixture was stirred at 70° C. for 10hours and cooled to room temperature, to afford1-(6-chloro-1-dimethylsulfamoyl-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester. To crude reaction mixture was added LiOH.H₂O (124 g,2.95 mol, 5.0 equiv.) in 2.5 L water. The reaction solution was heatedat 70° C. for 6 hours and then cooled to room temperature. ConcentratedHCl was added to adjust pH=4.0. The precipitated solid was collected byfiltration, washed with water and dried. The solid was recrystallizedfrom hot EtOAc (˜3 L). After cooling to room temperature and filtration,the pure compound was obtained as a white solid (109 g, 0.31 mol, 54%over 3 steps). MS (ESI/CI): mass calcd. for C₁₂H₆ClF₃N₄O₂, 346.0; m/zfound, 347.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 13.79 (s, 1H), 13.06 (s,1H), 8.91 (s, 1H), 8.33 (s, 1H), 7.79 (br d, 2H).

Example 114: 1-(1H-Naphtho[2,3-d]imidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 60Steps C-H, substituting 4-chloro-5-m-tolylsulfanyl-benzene-1,2-diaminefor naphthalene-2,3-diamine in Step C. MS (ESI/CI): mass calcd. forC₁₅H₁₀N₄O₂, 278.1; m/z found, 279.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):13.12-12.83 (m, 1H), 9.00 (d, J=0.6 Hz, 1H), 8.34 (d, J=0.6 Hz, 1H),8.06 (s, 2H), 8.01 (dd, J=6.3, 3.3 Hz, 2H), 7.40 (dd, J=6.4, 3.2 Hz,2H).

Example 115: 1-(3H-Naphtho[1,2-d]imidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 60Steps C-H, substituting 4-chloro-5-m-tolylsulfanyl-benzene-1,2-diaminefor naphthalene-1,2-diamine in Step C. MS (ESI/CI): mass calcd. forC₁₅H₁₀N₄O₂, 278.1; m/z found, 279.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):12.92 (s, 1H), 8.95 (d, J=0.6 Hz, 1H), 8.51 (d, J=8.0 Hz, 1H), 8.32 (d,J=0.5 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.75 (q, J=8.8 Hz, 2H), 7.67-7.59(m, 1H), 7.51 (ddd, J=8.2, 6.9, 1.2 Hz, 1H).

Example 116:1-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A:1-[5-fluoro-1-(2-methoxy-ethoxymethyl)-4-methyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. The titled compound was prepared in a manner analogousto EXAMPLE 60, Steps B-F substituting3-fluoro-2-methyl-6-nitro-phenylamine for4-chloro-2-nitro-5-m-tolylsulfanyl-phenylamine in Step B and lithiumdiisopropylamide for buthyllithium in Step E. MS (ESI/CI): mass calcd.for C₁₈H₂₁FN₄O₄, 376.2; m/z found, 377.1 [M+H]⁺.

Step B:1-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. A mixture of1-[5-fluoro-1-(2-methoxy-ethoxymethyl)-4-methyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.131 g, 0.481 mmol), glacial acetic acid (4.8 mL),and 6M aqueous HCl (4.8 mL) was heated at 100° C. for 4 h in a sealedtube. The reaction mixture was cooled to 23° C. and then 0° C. Theresulting precipitate was filtered and washed with cold water to yieldthe titled compound (75.0 mg, 60%). MS (ESI/CI): mass calcd. forC₁₂H₉FN₄O₂, 260.1; m/z found, 261.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):8.88 (s, 1H), 8.29 (s, 1H), 7.35 (dd, J=8.7, 4.5 Hz, 1H), 7.06 (dd,J=10.4, 8.8 Hz, 1H), 2.46 (d, J=1.3 Hz, 3H).

Example 117:1-(5-Piperidin-1-yl-6-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: 2-nitro-5-piperidin-1-yl-4-trifluoromethoxy-phenylamine.Piperidine (1.2 mL) was added to5-chloro-2-nitro-4-trifluoromethoxy-phenylamine (0.757 g, 2.94 mmol) ina sealed tube and the mixture was heated to 100° C. for 2 h. The mixturewas cooled to 23° C., poured into water (50 mL) and extracted with EtOAc(3×80 mL). The combined organic layers were washed with brine (50 mL),dried, filtered, and concentrated under reduced pressure to yield thetitled compound (0.900 g, 99.9%). MS (ESI/CI): mass calcd. forC₁₂H₁₄F₃N₃O₃, 305.1; m/z found, 306.1 [M+H]⁺.

Step B: 5-piperidin-1-yl-6-trifluoromethoxy-1H-benzoimidazole. A mixtureof 2-nitro-5-piperidin-1-yl-4-trifluoromethoxy-phenylamine (0.900 g,2.94 mmol), sodium dithionite (2.67 g, 15.3 mmol), trimethylorthoformate (8.72 mL, 79.6 mmol), DMF (8.56 mL), and acetic acid (1.45mL) was heated in a sealed tube for 15 h at 100° C. The reaction mixturewas cooled to 23° C. and partitioned between EtOAc (80 mL) and saturatedaqueous NaHCO₃ (80 mL). The organic layer was collected and the aqueouslayer was extracted with EtOAc (2×80 mL). The combined organic layerswere dried, filtered, and concentrated under reduced pressure. Theresidue was purified (FCC) (0-15% MeOH/DCM) to yield the titled compound(0.589 g, 71%). MS (ESI/CI): mass calcd. for C₁₃H₁₄F₃N₃O, 285.1; m/zfound, 286.1 [M+H]⁺.

Step C:1-[1-(2-methoxy-ethoxymethyl)-5-piperidin-1-yl-6-trifluoromethoxy-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. The titled compound was prepared as a 1:1 mixture ofregioisomers in a manner analogous to EXAMPLE 60, Steps D-F substitutinglithium diisopropylamide for buthyllithium in Step E. MS (ESI/CI): masscalcd. for C₂₃H₂₈F₃N₅O₅, 511.2; m/z found, 512.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 8.82 (d, J=0.6 Hz, 1H), 8.80 (d, J=0.6 Hz, 1H), 8.17-8.15(m, 2H), 7.56-7.55 (m, 1H), 7.48-7.46 (m, 1H), 7.36 (s, 1H), 7.19 (s,1H), 6.08 (s, 2H), 6.07 (s, 2H), 4.39-4.32 (m, 4H), 3.67-3.61 (m, 4H),3.48-3.42 (m, 4H), 3.31 (s, 3H), 3.30 (s, 3H), 3.05-2.95 (m, 8H),1.79-1.70 (m, 8H), 1.63-1.55 (m, 4H), 1.41-1.34 (m, 6H).

Step D:1-(5-Piperidin-1-yl-6-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. A mixture of1-[1-(2-methoxy-ethoxymethyl)-5-piperidin-1-yl-6-trifluoromethoxy-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.300 g, 0.586 mmol), glacial acetic acid (5.9 mL),and 6M aqueous HCl (6.9 mL) was heated at 100° C. for 4.5 h in a sealedtube. The reaction mixture was cooled to 23° C. and then 0° C. Theresulting precipitate was filtered and washed with cold water to yieldthe titled compound (60.0 mg, 26%). MS (ESI/CI): mass calcd. forC₁₇H₁₆F₃N₅O₃, 395.1; m/z found, 396.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):8.84 (d, J=0.6 Hz, 1H), 8.27 (d, J=0.6 Hz, 1H), 7.47 (br s, 1H), 7.21(br s, 1H), 2.98-2.89 (m, 4H), 1.71-1.59 (m, 4H), 1.58-1.47 (m, 2H).

Example 118:1-(5-Fluoro-6-piperidin-1-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 117,substituting 2-nitro-4,5-difluoroaniline for2-nitro-4-trifluoromethoxy-5-chloroaniline in Step A. MS (ESI/CI): masscalcd. for C₁₆H₁₆FN₅O₂, 329.1; m/z found, 330.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 8.88 (s, 1H), 8.28 (s, 1H), 7.99 (brs, 1H), 7.56 (d, J=12.2Hz, 1H), 3.39 (br s, 4H), 1.93 (br s, 4H), 1.64 (br m, 2H).

Example119:1-(6-Ethoxy-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was in a manner analogous to EXAMPLE 117,substituting 2-nitro-4,5-difluoroaniline for2-nitro-4-trifluoromethoxy-5-chloroaniline and sodium ethoxide (21 wt %solution in ethanol) for piperidine in Step A. MS (ESI/CI): mass calcd.for C₁₃H₁₁FN₄O₃, 290.1; m/z found, 291.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): 13.63-12.41 (m, 2H), 8.82 (s, 1H), 8.25 (s, J=0.5 Hz, 1H),7.61-6.97 (m, 2H), 4.13 (q, J=7.0 Hz, 2H), 1.38 (t, J=6.9 Hz, 3H).

Example 120:1-(5-Phenylcarbamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: 2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methylester. To a solution of 3,4-diamino-benzoic acid methyl ester (5.00 g,30.1 mmol) and THF (40 mL), was added carbonyl diimidazole (7.32 g, 45.1mmol) at 0° C. The mixture stirred for 16 h, and allowed to warm to 23°C. A solution of 1M aq. HCl (50 mL) was added at 0° C., followed bywater (70 mL) and the mixture was stirred for 1 h. The resultingprecipitate was filtered and dried under reduced pressure for 18 h toyield the titled compound, which was used in the next step withoutfurther purification (5.45 g, 94%). MS (ESI/CI): mass calcd. forC₉H₈N₂O₃, 192.1; m/z found, 193.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 11.01(s, 1H), 10.84 (s, 1H), 7.63 (dd, J=8.2, 1.6 Hz, 1H), 7.47 (s, 1H), 7.02(d, J=8.2 Hz, 1H), 3.82 (s, 3H).

Step B: 2-chloro-1H-benzoimidazole-5-carboxylic acid methyl ester.2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester (3.00g, 15.6 mmol) and phosphorus oxychloride (30 mL) were combined andheated to 100° C. for 48 h. The mixture was cooled to 23° C. andconcentrated under reduced pressure. The residue was cooled to 0° C.,and cold, saturated aqueous NaHCO₃ (60 mL) was added cautiously. Afterstirring at 23° C. for 15 min, the mixture was sonicated and theresulting residue was filtered to yield the titled compound (3.13 g,95%), which was used in the next step without further purification. MS(ESI/CI): mass calcd. for C₉H₇ClN₂O₂, 210.02; m/z found, 211.0 [M+H]⁺.

Step C:2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole-5-carboxylic acidmethyl ester. To a mixture of 2-chloro-1H-benzoimidazole-5-carboxylicacid methyl ester (2.00 g, 9.50 mmol) and THF (17 mL) was added DIPEA(2.46 mL, 14.3 mmol) followed by 1-chloromethoxy-2-methoxy-ethane (1.30mL, 11.4 mmol) at 23° C. After stirring for 18 h the reaction mixturewas concentrated under reduced pressure. The residue was purified (FCC)(5-50% EtOAc/hexanes) to yield the titled compound as a mixture ofregioisomers (1.71 g, 60%). MS (ESI/CI): mass calcd. for C₁₃H₁₅ClN₂O₄,298.1; m/z found, 299.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.34-8.31 (m,1H), 8.21-8.20 (m, 1H), 7.98 (dd, J=8.6, 1.6 Hz, 1H), 7.91 (dd, J=8.5,1.6 Hz, 1H), 7.83 (dd, J=8.6, 0.5 Hz, 1H), 7.74 (dd, J=8.5, 0.5 Hz, 1H),5.78 (s, 1H), 5.73 (s, 1H), 3.89 (d, J=6.3 Hz, 6H), 3.64-3.60 (m, 5H),3.43-3.39 (m, 5H), 3.17 (d, J=2.6 Hz, 6H).

Step D:2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole-5-carboxylic acid.To a mixture of2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole-5-carboxylic acidmethyl ester (0.600 g, 0.200 mmol), THF (10 mL), and water (3.33 mL),was added LiOH.H₂O (47.0 mg, 1.96 mmol). The mixture was stirred 18 h at23° C. The solvent was evaporated, water (5 mL) was added and themixture acidified to with 1 M HCl. The resulting white precipitate wasfiltered and dried to yield the titled compound (0.490 g, 86%). MS(ESI/CI): mass calcd. for C₁₂H₁₃ClN₂O₄, 284.1; m/z found, 285.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): 12.93 (s, 2H), 8.30 (s, 1H), 8.18 (d, J=1.4Hz, 1H), 7.96 (dd, J=8.6, 1.5 Hz, 1H), 7.90 (dd, J=8.5, 1.6 Hz, 1H),7.80 (d, J=8.6 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 5.74 (d, J=17.5 Hz, 4H),3.64-3.60 (m, 4H), 3.43-3.39 (m, 4H), 3.18 (d, J=0.6 Hz, 6H).

Step E:2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole-5-carboxylic acidphenylamide. To a solution of2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole-5-carboxylic acid(0.235 g, 0.825 mmol) and acetonitrile (4 mL) was added HATU (0.408 g,1.07 mmol). The resulting suspension was stirred at 23° C. for 5 min,treated with DIPEA (0.428 mL, 2.48 mmol) and stirred for an additional20 minutes. The reaction mixture was then treated with aniline (90.0 μL,0.990 mmol) and stirred for 2 h. The reaction mixture was diluted withwater (10 mL) and extracted with EtOAc (3×20 mL). The combined organiclayers were washed with brine, dried, filtered, and concentrated underreduced pressure. The residue was purified (FCC) (5-70% EtOAc/hexanes)to yield the titled compound (0.265 g, 89%) as a mixture ofregioisomers. MS (ESI/CI): mass calcd. for C₁₈H₁₈ClN₃O₃, 359.1; m/zfound, 360.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 10.26 (d, J=7.5 Hz, 2H),8.32 (dd, J=3.6, 1.5 Hz, 2H), 7.99 (dd, J=8.6, 1.6 Hz, 1H), 7.94 (dd,J=8.5, 1.6 Hz, 1H), 7.87-7.73 (m, 6H), 7.41-7.32 (m, 4H), 7.16-7.02 (m,2H), 5.75 (d, J=8.6 Hz, 4H), 3.67-3.61 (m, 4H), 3.43 (ddd, J=6.3, 4.7,3.1 Hz, 4H), 3.19 (d, J=1.5 Hz, 6H).

Step F:1-(5-phenylcarbamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27, Steps E-G. MS (ESI/CI): mass calcd. for C₁₈H₁₃N₅O₃, 347.1; m/zfound, 348.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.73 (s, 1H), 12.93 (s,1H), 10.25 (s, 1H), 8.94 (s, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 7.90 (d,J=8.4 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.68 (s, 1H), 7.36 (t, J=7.9 Hz,2H), 7.10 (t, J=7.2 Hz, 1H).

Example 121:1-(5-Benzylcarbamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 120,substituting benzylamine for aniline in Step E. MS (ESI/CI): mass calcd.for C₁₉H₁₅N₅O₃, 361.1; m/z found, 362.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆): 13.63 (s, 1H), 12.93 (s, 1H), 9.08 (s, 1H), 8.92 (s, 1H), 8.31(s, 1H), 8.22 (s, 0.5H), 8.05 (s, 0.5H), 7.85 (s, 1H), 7.70 (s, 0.5H),7.55 (s, 0.5H), 7.44-7.27 (m, 4H), 7.25 (s, 1H), 4.51 (d, J=5.9 Hz, 2H).

Example 122:1-[5-(Morpholin-4-ylcarbamoyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 120,substituting morpholin-4-ylamine for aniline in Step E. MS (ESI/CI):mass calcd. for C₁₆H₁₆N₆O₄, 356.1; m/z found, 357.1 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 12.95 (s, 1H), 9.56 (s, 1H), 8.92 (s, 1H), 8.31 (s, 1H),8.02 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 3.68 (s,6H), 2.93 (s, 5H).

Example 123:1-(5-Benzyloxymethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A:[2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-5-yl]-methanol. Toa stirred solution of2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole-5-carboxylic acidmethyl ester (Intermediate from EXAMPLE 120, product of Step C) (0.500g, 1.67 mmol) and THF (30 mL) was added lithium aluminum hydride (2M inTHF, 0.836 mL) dropwise over 10 min at 0° C. The reaction mixture wasstirred for 48 h, warming to 23° C. The reaction mixture was cooled to0° C., water (20 mL) was added and the resulting mixture was acidifiedwith 1M HCl.

The product was extracted with EtOAc (3×40 mL) and the combined organiclayers were washed with brine, dried, filtered, and concentrated underreduced pressure.

The residue was purified (FCC) (5-80% EtOAc/hexanes) to yield the titledcompound (0.356 g, 78%) as a 1:1 mixture of regioisomers. MS (ESI/CI):mass calcd. for C₁₂H₁₅ClN₂O₃, 270.1; m/z found, 271.1 [M+H]⁺. ¹H (600MHz, CDCl₃): 7.65-7.61 (m, 2H), 7.52 (s, J=0.7 Hz, 1H), 7.45 (d, J=8.3Hz, 1H), 7.35 (dd, J=8.3 Hz, 1.5 Hz, 1H), 7.27 (dd, J=8.2 Hz, 1.5 Hz,1H), 5.63 (s, 2H), 5.62 (s, 2H), 4.81 (s, 2H), 4.77 (s, 2H), 3.64-3.60(m, 4H), 3.49 (dd, J=5.4 Hz, 3.6 Hz, 4H), 3.35 (s, 3H), 3.34 (s, 3H),2.59 (s, 1H), 2.50 (s, 1H).

Step B:5-Benzyloxymethyl-2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole.To a solution of[2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-5-yl]-methanol(100 mg, 0.370 mmol) and DMF (3 mL) was added NaH (30.0 mg, 0.740 mmol,60% suspension in mineral oil) at 0° C. The reaction mixture was stirredfor 1 h at 0° C., then treated with benzyl bromide (52.0 μL, 0.440mmol). The reaction mixture was stirred for 16 h. Water (5 mL) was addedand the product was extracted with EtOAc (3×20 mL). The combined organiclayers were washed with brine, dried, filtered, and concentrated underreduced pressure. The residue was purified (FCC) (5-50% EtOAc/hexanes)to provide the titled compound (100 mg, 75%). MS (ESI/CI): mass calcd.for C₁₉H₂₁ClN₂O₃, 360.1; m/z found, 361.1 [M+H]⁺

Step C: Preparation of1-(5-benzyloxymethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27 Steps E-G. MS (ESI/CI): mass calcd. for C₁₉H₁₆N₄O₃, 348.1; m/z found,349.1 [M+H]‘ ’H NMR (600 MHz, DMSO-d₆): 13.31 (s, 1H), 12.93 (s, 1H),8.88 (s, 1H), 8.27 (s, 1H), 7.62 (s, 1H), 7.48 (s, 1H), 7.39-7.35 (m,4H), 7.32-7.21 (m, 2H), 4.64 (s, 2H), 4.55 (s, 2H).

Example124:1-(4-Bromo-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: 1-Benzoyl-3-(2,6-dibromo-4-fluoro-phenyl)-thiourea. A mixture of2,6-dibromo-4-fluoro-phenylamine (1.00 g, 3.72 mmol), benzoylisothiocyanate (0.600 ml, 4.46 mmol), dimethyl-pyridin-4-yl-amine (45.0g, 0.370 mmol), and toluene (5 ml) was stirred at 23° C. for 16 hours.The resulting precipitate was collected by filtration and washed withhexane to yield titled compound (1.37 g, 85%). MS (ESI/CI): mass calcd.for C₁₄H₉Br₂FN₂OS, 429.9; m/z found, 430.9 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD-d₄): 8.05-7.98 (m, 2H), 7.73-7.66 (m, 1H), 7.62-7.55 (m, 4H).

Step B: (2,6-Dibromo-4-fluoro-phenyl)-thiourea. To a solution of1-benzoyl-3-(2,6-dibromo-4-fluoro-phenyl)-thiourea (1.37 g, 3.17 mmol)in MeOH (12 mL) was added dropwise a sodium methoxide solution (5.4M inMeOH, 1.29 mL, 6.96 mmol) at 0° C. The mixture was warmed to 23° C. andstirred for 16 hours. MeOH was concentrated under reduced pressure. Theresidue was dissolved in water, cooled to 0° C., and acidified to pH 4with 1M HCl. The resulting precipitate was collected by filtration andwashed with hexanes to yield titled compound (1.04 g, 99%). MS (ESI/CI):mass calcd. for C₇H₅Br₂FN₂S, 325.9; m/z found, 326.9 [M+H]⁺. ¹H NMR (400MHz, CD₃OD-d₄): 8.05-8.01 (m, 2H).

Step C: 2,6-Dibromo-4-fluoro-phenyl-cyanamide. A solution of(2,6-dibromo-4-fluoro-phenyl)-thiourea (0.300 g, 0.920 mmol) and 1M aq.KOH (7.23 mL) was heated to 100° C. Lead (II) acetate trihydrate (0.400g, 1.05 mmol) in water (2 mL) was then added. The mixture was heated at100° C. for another 10 minutes while a precipitate was observed. Themixture was cooled to 0° C. and filtered to provide a clear colorlesssolution. The filtrate was acidified to pH 5 with acetic acid. Theprecipitate was collected by filtration to yield titled compound (0.170g, 63%). ¹H NMR (400 MHz, DMSO-d₆): 7.80-7.78 (m, 2H).

Step D:1-[N-(2,6-Dibromo-4-fluoro-phenyl)-carbamimidoyl]-1H-pyrazole-4-carboxylicacid ethyl ester. A mixture of 2,6-dibromo-4-fluoro-phenyl-cyanamide(0.167 g, 0.570 mmol), ethyl pyrazole-4-carboxylate (80.0 mg, 0.570mmol), 4M HCl in dioxane (0.156 mL, 0.630 mmol), and 1,4 dioxane (2 mL)was heated to reflux for 2 h, during which time a precipitate formed.The mixture was allowed to cool to 23° C. Et₂O (10 mL) was added to themixture. The resulting precipitate was collected by filtration, washedwith Et₂O, and dried to yield the titled compound (0.134 g, 50%) as theHCl salt. MS (ESI/CI): mass calcd. for C₁₃H₁₁Br₂FN₄O₂, 431.9; m/z found,432.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.20 (s, 1H), 7.43 (s, 1H),6.82 (d, J=7.9 Hz, 2H), 3.56 (q, J=7.1 Hz, 2H), 2.85 (s, 3H), 0.57 (t,J=7.1 Hz, 3H).

Step E:1-(4-Bromo-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acidethyl ester. A mixture of1-[N-(2,6-dibromo-4-fluoro-phenyl)-carbamimidoyl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.134 g, 0.290 mmol), CuI (6.00 mg, 0.0290 mmol),Cs₂CO₃ (0.464 g, 1.43 mmol), and DMF (2 mL) was heated to 80° C. for 1h. The mixture was cooled to 23° C., diluted with EtOAc (3 mL), filteredthrough Celite®, and rinsed with EtOAc. The filtrate was washed withaqueous 1M HCl and water, dried (MgSO₄), filtered, and concentratedunder reduced pressure. Dichloromethane was added and the resultingprecipitate was collected by filtration to yield the titled compound(17.0 mg, 17%). MS (ESI/CI): mass calcd. for C₁₃H₁₀BrFN₄O₂, 353.2; m/zfound, 354.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.86 (s, 1H), 8.95 (s,1H), 8.36 (s, 1H), 7.45 (dd, J=9.6, 2.3 Hz, 1H), 7.32 (s, 1H), 4.30 (q,J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).

Step F:1-(4-Bromo-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. A mixture of1-(4-bromo-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acidethyl ester (16.0 mg, 45.0 mmol), LiOH (10.0 mg, 0.230 mmol), THF (0.5mL), and H₂O (0.17 mL) was stirred at 23° C. for 16 h. THF was removedunder reduced pressure and then aqueous HCl was added. The resultingprecipitate was collected and washed with water to yield the titledcompound (10.0 mg, 67%). MS (ESI/CI): mass calcd. for C₁₁H₆BrFN₄O₂,325.1; m/z found, 326.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.82 (s,1H), 12.94 (s, 1H), 8.87 (s, 1H), 8.30 (d, J=0.5 Hz, 1H), 7.45 (dd,J=9.6, 2.3 Hz, 1H), 7.32 (s, 1H).

Example 125:1-(8H-Imidazo[4′,5′:3,4]benzo[2,1-d]thiazol-7-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 124,Steps A-E, substituting 4-bromo-benzothiazol-5-ylamine for2,6-dibromo-4-fluoro-phenylamine in Step A. The following modificationswere made in Step E:

Step E:1-(8H-imidazo[4′,5′:3,4]benzo[2,1-d]thiazol-7-yl)-1H-pyrazole-4-carboxylicacid ethyl ester. The hydrochloride salt of1-[N-(4-bromo-benzothiazol-5-yl)-carbamimidoyl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.128 g, 0.297 mmol), 1,10-phenanthroline (10.7 mg,59.4 μmol), cesium carbonate (0.290 g, 0.891 mmol), and DME (5.5 mL)were combined in a sealable microwave tube. The tube was sparged withdry nitrogen and copper (I) iodide (5.70 mg, 29.7 μmol) was added. Thereaction mixture was further sparged and the tube was sealed and heatedat 80° C. for 1.75 h. The reaction mixture was partitioned between 1Maq. HCl (15 mL) and EtOAc (25 mL). The aqueous layer was furtherextracted with EtOAc (2×20 mL) and the combined organic layers werewashed with brine (10 mL), dried, filtered, and concentrated underreduced pressure. The residue was purified (FCC) (10-60% EtOAc/hexanes,dry-loaded), the clean fractions were concentrated and the residuetriturated with diethyl ether to yield the titled compound (19.5 mg, 21%yield). MS (ESI/CI): mass calcd. for C₁₄H₁₁N₅O₂S, 313.1; m/z found,314.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.75 (s, 1H), 9.45 (s, 1H),9.05 (s, 1H), 8.37 (s, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.65 (d, J=6.0 Hz,1H), 4.31 (q, J=7.0 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H).

Step F:1-(8H-Imidazo[4′,5′:3,4]benzo[2,1-d]thiazol-7-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE124, Step F. MS (ESI/CI): mass calcd. for C₁₂H₇N₅O₂S, 285.0; m/z found,286.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 12.94 (brs, 1H), 9.46 (s, 1H),8.98 (d, J=0.47 Hz, 1H), 8.31 (s, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.69 (d,J=8.5 Hz, 1H).

Example 126:1-(5,6-Bis-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 124,substituting 2-bromo-4,5-bis-trifluoromethyl-phenylamine for2,6-dibromo-4-fluoro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₃H₆F₆N₄O₂, 364.0; m/z found, 365.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):14.29 (s, 1H), 13.06 (s, 1H), 8.97 (d, J=0.4 Hz, 1H), 8.37 (s, 1H), 8.15(s, 2H).

Example 127:1-(4,5,6-Trichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid

Step A: 2,3,4-Trichloro-6-nitro-phenylamine. A mixture of4,5-dichloro-2-nitro-phenylamine (0.500 g, 2.42 mmol),N-chlorosuccinimide (0.403 g, 3.02 mmol), and DMF (5 mL) was heated to100° C. for 1 h. After cooling to 23° C., the solution was poured intoice water. The yellow precipitate was collected by filtration anddissolved in dichloromethane. The organic phase was washed with water,dried (MgSO₄), filtered, and concentrated to yield the titled compound(0.468 g, 81%). ¹H NMR (400 MHz, CDCl₃): 8.28 (s, 1H), 6.70 (s, 2H). Thecompound did not yield MS data.

Step B: 4,5,6-Trichloro-1H-benzoimidazole. A mixture of2,3,4-trichloro-6-nitro-phenylamine (0.250 g, 1.04 mmol), sodiumdithionite (0.907 g, 5.21 mmol), trimethyl orthoformate (4 ml), DMF (4mL), and acetic acid (0.5 mL) was heated in a sealed tube for 15 h at100° C. The reaction mixture was cooled to 23° C. and partitionedbetween EtOAc and saturated aqueous NaHCO₃. The organic layer wascollected and the aqueous layer was extracted with EtOAc. The combinedorganic layers were dried (MgSO₄), filtered, and concentrated to yieldthe titled compound (0.098 g, 43%). MS (ESI/CI): mass calcd. forC₇H₃Cl₃N₂, 219.9; m/z found, 221.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):13.16 (s, 1H), 8.43 (s, 1H), 7.90 (s, 1H).

Step C: 4,5,6-Trichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole. Toa mixture of 4,5,6-trichloro-1H-benzoimidazole (0.098 g, 0.446 mmol) andTHF (2.5 mL) was added DIPEA (0.155 mL, 0.892 mmol), followed by1-chloromethoxy-2-methoxy-ethane (0.057 ml, 0.49 mmol) at 23° C. Afterstirring for 18 h, EtOAc was added. The organic layer was washed withsaturated aqueous NaHCO₃. The aqueous layer was further extracted withEtOAc. The organic layer was dried over MgSO₄, filtered, andconcentrated under reduced pressure. The residue was purified (FCC) toyield the titled compound as a mixture of regioisomers (0.084 g, 61%).MS (ESI/CI): mass calcd. for C₁₁H₁₁Cl₃N₂O₂, 308.0; m/z found, 309.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.59 (s, 1H), 8.58 (s, 1H), 8.09 (s,1H), 8.04 (d, J=8.5 Hz, 1H), 5.84 (s, 2H), 5.71 (s, 2H), 3.59-3.57 (m,2H), 3.56-3.53 (m, 2H), 3.42-3.38 (m, 4H), 3.18 (s, 3H), 3.17 (s, 3H).

Step D:2,4,5,6-Tetrachloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole. Asolution of 4,5,6-trichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole(0.388 g, 1.26 mmol) and THF (6 mL) was cooled to −78° C. in anacetone/dry ice bath. Lithium diisopropylamide (1.0 M solution in THF,2.52 mL, 2.52 mmol) was added dropwise and the reaction mixture wasstirred at −78° C. for 1 h. A solution of N-chlorosuccinimide (0.336 g,2.52 mmol) and THF (2 mL) was added. The reaction mixture was warmed to23° C. and stirred for 2 h. Saturated aqueous NH₄Cl was added and thecrude product was extracted with EtOAc. The combined organic layers weredried, filtered, and concentrated under reduced pressure. The residuewas purified (FCC) to yield the titled compound as a mixture ofregioisomers (0.267 g, 62%). MS (ESI/CI): mass calcd. for C₁₁H₁₀Cl₄N₂O₂,342.0; m/z found, 343.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.18 (s, 1H),8.03 (s, 1H), 5.88 (d, J=5.8 Hz, 2H), 5.71 (s, 2H), 3.71-3.66 (m, 2H),3.64-3.61 (m, 2H), 3.44-3.38 (m, 4H), 3.17 (t, J=1.7 Hz, 6H).

Step E:1-[4,5,6-Trichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. A mixture of2,4,5,6-tetrachloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole (0.275g, 0.80 mmol), Cs₂CO₃ (0.524 g, 1.61 mmol), 1H-pyrazole-4-carboxylicacid ethyl ester (0.124 g, 0.89 mmol), and DMF (4 mL) was heated to 80°C. for 2 h. The mixture was cooled to 23° C. EtOAc was added and themixture was washed with brine. The organic layer was dried (MgSO₄),filtered, and concentrated under reduced pressure. The residue waspurified (FCC) to yield the titled compound as a mixture of regioisomers(0.166 g, 46%). MS (ESI/CI): mass calcd. for C₁₇H₁₇Cl₃N₄O₄, 446.0; m/zfound, 447.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 9.01-8.97 (m, 2H), 8.40(t, J=2.3 Hz, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 6.09 (s,2H), 6.01 (s, 2H), 4.30 (qd, J=7.1 Hz, 2.9, 8H), 3.58-3.51 (m, 2H), 3.44(d, J=4.9 Hz, 2H), 3.11 (s, 3H), 3.08 (s, 3H), 1.32 (tt, J=7.1 Hz, 1.7Hz, 6H).

Step F:1-(4,5,6-Trichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.To a stirred solution of1-[4,5,6-trichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.166 g, 0.372 mmol) and acetic acid (6 mL) was added6M aq. hydrochloric acid (6 mL). The reaction mixture was heated to 100°C. for 18 h and then cooled to 23° C. The precipitate was collected toyield the titled compound as the HCl salt (0.91 g, 74% yield). MS(ESI/CI): mass calcd. for C₁₁H₅Cl₃N₄O₂, 330.0; m/z found, 331.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): 8.92 (s, 1H), 8.34 (s, 1H), 7.74 (s, 1H).

Example 128:1-(4-Bromo-5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A:1-[4-Bromo-5,6-dichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. The titled compound was prepared in a manner analogousto EXAMPLE 127, Steps A-E, substituting N-chlorosuccinimide withN-bromosuccinimide in Step A. MS (ESI/CI): mass calcd. forC₁₇H₁₇BrCl₂N₄O₄, 490.0; m/z found, 491.0 [M+H]⁺. Step B:1-(4-Bromo-5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester. To a mixture of1-[4-bromo-5,6-dichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.132 g, 0.27 mmol) and EtOH (2 mL) was added 4M HClin dioxane (2 mL). The mixture was stirred for 18 h at 23° C. Theresulting white precipitate was filtered and washed with EtOH to yieldthe titled compound (0.088 g, 81%). MS (ESI/CI): mass calcd. forC₁₃H₉BrCl₂N₄O₄, 402.9; m/z found, 403.9 [M+H]+. ¹H NMR (500 MHz,DMSO-d₆): 14.22-13.94 (m, 1H), 8.98 (s, 1H), 8.40 (s, 1H), 7.74 (s, 1H),4.30 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).

Step C:1-(4-Bromo-5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. LiOH.H₂O (0.046 g, 1.09 mmol) was added to a mixture of1-(4-Bromo-5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester (0.088 g, 0.22 mmol), THF (1 mL), and water (0.33 mL),and the mixture was stirred 18 h at 23° C. The solvent was evaporated,water (3 mL) was added and the mixture acidified with 1M HCl. Theresulting white precipitate was filtered and dried to yield the titledcompound (0.068 g, 83%). MS (ESI/CI): mass calcd. for C₁₁H₅BrCl₂N₄O₂,374.9; m/z found, 375.9 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 8.89 (s, 1H),8.32 (s, 1H), 7.74 (s, 1H).

Example 129:1-(6-Fluoro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: N-(3-Fluoro-4-trifluoromethyl-phenyl)-acetamide. To a mixture of3-fluoro-4-trifluoromethyl-phenylamine (16.9 g, 92.6 mmol),N,N-dimethyl-4-aminopyridine (1.13 g, 9.26 mmol), and toluene (230 mL)was added acetic anhydride (13.1 mL, 0.139 mol). The reaction mixturewas heated at reflux for 3 h, and stirred at 23° C. for 16 h. Thereaction mixture was concentrated and the crude product was dissolved inEtOAc (100 mL). The organic layer was washed with water (40 mL) andbrine (40 mL), dried, filtered, and concentrated under reduced pressure.The crude solid was triturated from DCM/hexanes to yield the titledcompound (16.5 g, 81% yield). MS (ESI/CI): mass calcd. for C₉H₇F₄NO,221.1; m/z found, 222.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.68 (d, J=12.5Hz, 1H), 7.52 (t, J=8.3 Hz, 1H), 7.45 (br s, 1H), 7.19 (d, J=8.5 Hz,1H), 2.22 (s, 3H).

Step B: N-(5-Fluoro-2-nitro-4-trifluoromethyl-phenyl)-acetamide. To avigorously stirred solution ofN-(3-fluoro-4-trifluoromethyl-phenyl)-acetamide (0.663 g, 3.00 mmol) andsulfuric acid (3 mL) was added dropwise a solution of potassium nitrate(0.607 g, 6.00 mmol) and conc. sulfuric acid (3 mL) at 0° C. Thereaction mixture was stirred for 1 h at 0° C. and then slowly pipettedinto ice/water with stirring. The resulting precipitate was collectedand dried in vacuo to yield the titled compound (0.648 g, 81% yield) asa single regioisomer. The compound did not yield MS data. ¹H NMR (600MHz, CDCl₃): 10.67 (brs, 1H), 8.86 (d, J=12.9 Hz, 1H), 8.57 (d, J=7.2Hz, 1H), 2.35 (s, 3H).

Step C: 5-Fluoro-2-nitro-4-trifluoromethyl-phenylamine. A suspension ofN-(5-fluoro-2-nitro-4-trifluoromethyl-phenyl)-acetamide (17.8 g, 67.0mmol) in aqueous HCl (3M, 400 mL) was heated at reflux for 3 h. Theresulting suspension was cooled to 0° C. and brought to pH 8 withNaHCO₃. The resulting solid was collected to yield the titled compound(13.7 g, 91% yield). The compound did not yield MS data. ¹H NMR (400MHz, CDCl₃): 8.48 (d, J=7.3 Hz, 1H), 6.75-6.18 (m, 3H).

Step D:1-(6-Fluoro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE71, Steps B-C. MS (ESI/CI): mass calcd. for C₁₂H₆F₄N₄O₂, 314.0; m/zfound, 315.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD, tautomeric broadening):8.93 (s, 1H), 8.20 (s, 1H), 7.87 (br s, 1H), 7.49 (br s, 1H).

Example 130:1-(6-Chloro-5-ethylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A:1-[6-Chloro-5-ethylamino-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a slurry of 4 Å molecular sieves (1.2 g) and1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 41, product from Step A)(0.300 g, 0.762 mmol), and ethanol (3 mL) was added acetaldehyde (0.500mL, 8.91 mmol) at 0° C. in a sealable microwave tube. The tube wassealed and the reaction mixture was allowed to warm to 23° C. over 16 h.The reaction mixture was heated at 60° C. for 1 h. The molecular sieveswere removed from the resulting solution by filtration and the filtratewas concentrated under reduced pressure. Sodium triacetoxy borohydride(0.242 g, 1.14 mmol), THF (3 mL), and glacial acetic acid (0.04 mL) wereadded to the residue and the resulting suspension was stirred for 7.5 hat 23° C. The reaction mixture was concentrated and the residuepartitioned between saturated aqueous sodium bicarbonate and EtOAc (35mL). The aqueous layer was further extracted with EtOAc (2×35 mL) andthe combined organic layers were washed with brine (15 mL), dried,filtered, and concentrated under reduced pressure. The residue waspurified (FCC) (10-45% EtOAc/hexanes) to yield the titled compound(0.169 g, 47% crude yield). This compound was used without furtherpurification in subsequent reactions. MS (ESI/CI): mass calcd. forC₁₉H₂₄ClN₅O₄, 421.2; m/z found, 422.1 [M+H]⁺.

Step B:1-(6-Chloro-5-ethylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27, Steps F-G. MS (ESI/CI): mass calcd. for C₁₃H₁₂ClN₅O₂, 305.1; m/zfound, 306.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomeric broadening):8.84 (s, 1H), 8.27 (s, 1H), 7.60 (s, 1H), 7.03 (br s, 1H), 3.22 (q,J=6.9 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H).

Example 131:1-(6-Chloro-5-propylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A:1-[6-Chloro-5-ethylamino-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a solution of1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 41, product from Step A)(0.300 g, 0.762 mmol) and propionaldehyde (61.0 μL, 0.838 mmol) in THF(3 mL) was added sodium triacetoxyborohydride (0.226 g, 1.07 mmol)followed by acetic acid (40.9 μL, 0.762 mmol). The reaction mixture wasstirred at 23° C. for 22 h. Molecular sieves (4 Å, 1.2 g) were added,and the reaction was kept at 40-50° C. for 24 h. Over the next 48 h, twoadditional portions of both propionaldehyde and sodiumtriacetoxyborohydride were added. The reaction was quenched withsaturated aqueous sodium bicarbonate (10 mL). The aqueous layer wasextracted with EtOAc (3×35 mL) and the combined organic layers werewashed with brine (25 mL), dried, filtered, and concentrated underreduced pressure. The residue was purified (FCC) (10-45% EtOAc/hexanes)to yield the titled compound (0.178 g, 54% yield) as a 1:1 mixture ofregioisomers. ¹H NMR (400 MHz, CDCl₃): 8.83 (s, 1H), 8.76 (s, 1H), 8.15(s, 2H), 7.63 (s, 1H), 7.55 (s, 1H), 6.94 (s, 1H), 6.76 (s, 1H), 6.03(s, 4H), 4.42 (br s, 1H), 4.35 (q, J=7.1 Hz, 4H), 4.27 (br s, 1H),3.65-3.59 (m, 4H), 3.49-3.41 (m, 4H), 3.33 (s, 3H), 3.32 (s, 3H),3.23-3.12 (m, 4H), 1.82-1.69 (m, 4H), 1.37 (t, J=7.1 Hz, 6H), 1.11-1.01(m, 6H).

Step B:1-(6-Chloro-5-ethylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27, Steps F-G. MS (ESI/CI): mass calcd. for C₁₄H₁₄ClN₅O₂, 319.1; m/zfound, 320.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomeric broadening):12.91 (br s, 1H), 8.80 (s, 1H), 8.24 (s, 1H), 7.51 (br s, 1H), 6.71 (brs, 1H), 3.10 (t, J=7.1 Hz, 2H), 1.69-1.59 (m, 2H), 0.96 (t, J=7.4 Hz,3H).

Example 132:1-(5-Benzylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A:1-[5-(Benzylidene-amino)-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. Benzaldehyde (93.0 mg, 0.876 mmol),1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 41, product from Step A)(0.300 g, 0.762 mmol), THF (3 mL), and 4 Å molecular sieves (0.910 g)were combined and stirred for 18 h at 23° C. Sodiumtriacetoxyborohydride (0.242 g, 1.14 mmol) was added and stirring wascontinued for 4 days. The reaction was quenched with saturated aqueoussodium bicarbonate (15 mL) and stirred with dichloromethane (25 mL).This mixture was filtered and the layers were separated. The aqueouslayer was extracted with dichlormethane (2×25 mL) and the combinedorganic layers were washed with brine (20 mL), dried, filtered, andconcentrated under reduced pressure. The residue was purified (FCC)(10-45% EtOAc/hexanes) to yield the titled compound (0.288 g, 78% yield)as a 4:3 mixture of regioisomers. The titled compound was not stableenough to obtain a mass spectrum. ¹H NMR (400 MHz, CDCl₃): 8.87 (s, 1H),8.48 (s, 1H), 8.19 (s, 1H), 8.03-7.94 (m, 2H), 7.73 (s, 1H), 7.58-7.48(m, 3H), 7.39 (s, 1H), 6.12 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.7-3.6 (m,2H), 3.5-3.4 (m, 2H), 3.32 (s, 3H), 1.39 (t, J=7.1 Hz, 3H).

Step B:1-[5-Benzylamino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a slurry of1-[5-(benzylidene-amino)-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.177 g, 0.366 mmol) in ethanol (7 mL) was addedsodium borohydride (41.6 mg, 1.10 mmol) at 0° C. The yellow slurry waswarmed to 23° C. over 24 h. The reaction mixture was concentrated andsaturated aqueous sodium bicarbonate (25 mL) was added to the residue.The reaction mixture was extracted with EtOAc (3×25 mL) and the combinedorganic layers were washed with brine (20 mL), dried, filtered, andconcentrated under reduced pressure. The residue was purified (FCC)(10-45% EtOAc/hexanes) to yield the titled compound as a 6:5 mixture ofregioisomers (0.144 g, 81% yield). MS (ESI/CI): mass calcd. forC₂₄H₂₆ClN₅O₄, 483.2; m/z found, 484.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.79 (s, 1H), 8.14 (s, 1H), 7.58 (s, 1H), 7.43-7.27 (m, 5H), 6.92 (s,1H), 6.03 (s, 2H), 4.75 (t, J=6.0 Hz, 1H), 4.49-4.43 (m, 2H), 4.34 (q,J=7.2 Hz, 2H), 3.65-3.61 (m, 2H), 3.47-3.44 (m, 2H), 3.32 (s, 1H), 1.36(t, J=7.1 Hz, 3H).

Step C:1-(5-Benzylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27, Steps F-G. MS (ESI/CI): mass calcd. for C₁₈H₁₄ClN₅O₂, 367.1; m/zfound, 368.0 [M+H]+. ¹H NMR (400 MHz, DMSO-d₆, tautomeric broadening):12.87 (br s, 1H), 8.76 (d, J=0.5 Hz, 1H), 8.20 (s, 1H), 7.52 (br s, 1H),7.40-7.31 (m, 4H), 7.25-7.20 (m, 1H), 6.56 (br s, 1H), 6.00 (br s, 1H),4.44 (s, 2H).

Example 133:1-(6-Chloro-5-phenylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A:1-[6-Chloro-1-(2-methoxy-ethoxymethyl)-5-phenylamino-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. An oven-dried flask was charged with1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 41, product from Step A)(0.100 g, 0.254 mmol), bromobenzene (43.8 mg, 0.279 mmol), Pd(dba)₂(1.50 mg, 2.50 μmol), Q-Phos (3.60 mg, 5.10 μmol), and sodiumtert-butoxide (36.6 mg, 0.381 mmol). The flask was purged with N₂. Drytoluene (0.5 mL) was added and the slurry was briefly sonicated. Thereaction mixture was heated at 50° C. for 18 h. The reaction mixture wasthen diluted with dichloromethane and filtered through a pad of Celite®.The filter cake was rinsed with EtOAc and the filtrate was concentratedunder reduced pressure. The residue was purified (FCC) (10-45%EtOAc/hexanes) to yield the titled compound (7.1 mg, 6% yield), whichwas used in the next step without further purification. MS (ESI/CI):mass calcd. for C₂₃H₂₄ClN₅O₄, 469.2; m/z found, 470.1 [M+H]⁺.

Step B:1-(6-Chloro-5-phenylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27, Steps F-G. MS (ESI/CI): mass calcd. for C₁₇H₁₂ClN₅O₂, 353.1; m/zfound, 354.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomeric broadening):12.94 (brs, 1H), 8.86 (s, 1H), 8.28 (s, 1H), 7.74-7.69 (m, 2H), 7.40 (s,1H), 7.24-7.18 (m, 2H), 6.95 (d, J=7.8 Hz, 2H), 6.81 (t, J=7.3 Hz, 1H).

Example 134:1-[6-Chloro-5-(2-morpholin-4-yl-ethylamino)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

Step A:1-[6-Chloro-1-(2-methoxy-ethoxymethyl)-5-(2-morpholin-4-yl-ethylamino)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a slurry of 4 Å molecular sieves (0.9 g),1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 41, product from Step A)(0.187 g, 0.475 mmol), sodium 1-hydroxy-2-morpholin-4-yl-ethanesulfonate(0.122 g, 0.523 mmol) and THF (2.5 mL) was added triethylamine (0.300mL, 2.15 mmol). The slurry was stirred at 23° C. for 24 h, and sodiumtriacetoxyborohydride (0.282 g, 1.33 mmol) was added. The reactionmixture was stirred for an additional 24 h. Additional sodium1-hydroxy-2-morpholin-4-yl-ethanesulfonate (62.0 mg, 0.270 mmol) wasadded and the reaction was allowed to continue for another 24 h at 23°C. The reaction mixture was diluted with EtOAc, filtered, and washedwith saturated aqueous NaHCO₃. The aqueous layer was further extractedwith EtOAc (2×30 mL). The combined organic layers were washed withbrine, dried, filtered, and concentrated under reduced pressure. Theresidue was purified (FCC) (EtOAc/hexanes) to yield the titled compound(30 mg, 12% crude yield). This compound was used without furtherpurification in subsequent reactions. MS (ESI/CI): mass calcd. forC₂₃H₃₁ClN₆O₅, 506.2; m/z found, 507.2 [M+H]⁺.

Step B:1-[6-Chloro-5-(2-morpholin-4-yl-ethylamino)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27, Steps F-G. MS (ESI/CI): mass calcd. for C₁₇H₁₉ClN₆O₃, 390.1; m/zfound, 391.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD-d₄, tautomeric broadening):8.77 (s, 1H), 8.12 (s, 1H), 7.50 (br s, 1H), 6.86 (br s, 1H), 3.79-3.74(m, 4H), 3.38 (t, J=6.3 Hz, 2H), 2.89-2.82 (br m, 2H), 2.69 (br s, 4H).

Example 135:1-(6-Chloro-5-cyclopropanesulfonylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A:1-[6-Chloro-5-cyclopropanesulfonylamino-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a stirred solution of1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 41, product from Step A)(0.100 g, 0.254 mmol) in pyridine (1.5 mL) was added dropwisecyclopropanesulfonyl chloride (71.0 mg, 0.510 mmol) at 0° C. Thereaction mixture was slowly warmed to 23° C., and maintained at thistemperature for 42 h. The reaction was quenched with sat. aq. sodiumbicarbonate (10 mL) and extracted with EtOAc (3×15 mL). The combinedorganic layers were washed with brine (10 mL), dried, filtered, andconcentrated under reduced pressure. The residue was purified (FCC)(10-55% EtOAc/hexanes) to yield the titled compound (96.0 mg, 76%),which was recovered as a 5:4 mixture of regioisomers. MS (ESI/CI): masscalcd. for C₂₀H₂₄ClN₅O₆S, 497.1; m/z found, 498.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 8.83 (s, 1H), 8.19 (s, 1H), 8.03 (s, 1H), 7.71 (s, 1H),6.73 (s, 1H), 6.14 (s, 2H), 4.31-4.28 (m, 2H), 3.71-3.64 (m, 2H),3.51-3.45 (m, 2H), 3.32 (s, 3H), 2.54-2.44 (m, 1H), 1.43-1.35 (m, 3H),1.21-1.11 (m, 2H), 1.00-0.92 (m, 2H).

Step B: Preparation of1-(6-Chloro-5-cyclopropanesulfonylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE71, Step C. MS (ESI/CI): mass calcd. for C₁₄H₁₂ClN₅O₄S, 381.0; m/zfound, 382.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomeric broadening):13.55 (br s, 1H), 12.97 (br s, 1H), 9.46 (br s, 1H), 8.89 (s, 1H), 8.31(s, 1H), 7.94-7.45 (m, 2H), 2.69-2.59 (m, 1H), 0.98-0.79 (m, 4H).

Example 136:1-(6-Chloro-5-methanesulfonylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 135,substituting methanesulfonyl chloride for cyclopropanesulfonyl chloridein Step A. MS (ESI/CI): mass calcd. for C₁₂H₁₀ClN₅O₄, 355.0; m/z found,356.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 9.48 (s, 1H), 8.90 (s, 1H),8.31 (s, 1H), 7.72 (s, 1H), 7.61 (s, 1H), 3.01 (s, 3H).

Example 137:1-(6-Chloro-5-ethanesulfonylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 135,substituting ethanesulfonyl chloride for cyclopropanesulfonyl chloridein Step A. A 5:4 mixture of tautomers was observed in the ¹H NMRspectrum. MS (ESI/CI): mass calcd. for C₁₃H₁₂ClN₅O₄S, 369.0; m/z found,370.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.60-13.48 (m, 1H), 12.97 (brs, 1H), 9.46 (s, 1H), 8.89 (s, 1H), 8.31 (s, 1H), 7.85-7.52 (m, 2H),3.18-3.04 (m, 2H), 1.35-1.20 (m, 3H).

Example 138:1-(5-Benzenesulfonylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 135,substituting benzenesulfonyl chloride for cyclopropanesulfonyl chloridein Step A. MS (ESI/CI): mass calcd. for C₁₇H₁₂ClN₅O₄S, 417.0; m/z found,418.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.58-13.46 (m, 1H), 12.97 (brs, 1H), 10.02-9.90 (m, 1H), 8.93-8.81 (m, 1H), 8.29 (s, 1H), 7.70-7.42(m, 6H), 7.34 (s, 1H).

Example 139:1-(5-Acetylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A:1-[5-Acetylamino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a stirred suspension of1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 41, product from Step A)(0.300 g, 0.762 mmol) and THF (4 mL) was added diisopropylethylamine(0.330 mL, 1.90 mmol) at 0° C. Acetyl chloride (57.0 μL, 0.800 mmol) wasthen added. After 3 h, the reaction was quenched with water (10 mL) andextracted with EtOAc (3×35 mL). The combined organic layers were washedwith brine (15 mL), dried, filtered, and concentrated under reducedpressure. The residue was purified (FCC) (5-65% EtOAc/hexanes) to yieldthe titled compound (0.270 g, 81%) as a 2:1 mixture of regioisomers. MS(ESI/CI): mass calcd. for C₁₉H₂₂ClN₅O₅, 435.1; m/z found, 436.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.83 (s, 1H), 8.71 (s, 1H), 8.18 (s, 1H), 7.79(br s, 1H), 7.74 (s, 1H), 6.10 (s, 1H), 4.36 (q, J=7.1 Hz, 2H),3.66-3.62 (m, 2H), 3.48-3.43 (m, 2H), 3.29 (s, 3H), 2.29 (s, 3H), 1.38(t, J=7.1 Hz, 3H).

Step B:1-(5-Acetylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27, Steps F-G. MS (ESI/CI): mass calcd. for C₁₃H₁₀ClN₅O3, 319.1; m/zfound, 320.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 9.54 (s, 1H), 8.89 (s,1H), 8.94 (s, 1H), 8.30 (s, 1H), 7.82 (s, 1H), 7.69 (s, 1H), 2.11 (s,3H).

Example 140:1-(6-Chloro-5-propionylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared) in a manner analogous to EXAMPLE 139,substituting propionyl chloride for acetyl chloride in Step A. MS(ESI/CI): mass calcd. for C₁₄H₁₂ClN₅O3, 333.1; m/z found, 334.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-de, tautomeric broadening): 13.48 (br s, 1H),12.96 (br s, 1H), 9.41 (s, 1H), 8.88 (s, 1H), 8.30 (s, 1H), 7.93-7.43(m, 2H), 2.46-2.35 (m, 2H), 1.11 (t, J=7.6 Hz, 3H).

Example 141:1-(5-Benzoylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 139,substituting benzoyl chloride for acetyl chloride in Step A. MS(ESI/CI): mass calcd. for C₁₈H₁₂ClN₅O₃, 381.1; m/z found, 382.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): 12.96 (br s, 1H), 10.10 (s, 1H), 8.93 (s,1H), 8.32 (s, 1H), 8.06-8.00 (m, 2H), 7.78-7.72 (m, 2H), 7.65-7.51 (m,3H).

Example 142:1-[6-Chloro-5-(2-morpholin-4-yl-acetylamino)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

Step A:1-[5-(2-Bromo-acetylamino)-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a solution of diisopropylethylamine (0.86 mL, 4.95mmol),1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 41, product from Step A)(0.650 g, 1.65 mmol), and THF (8 mL) at 0° C., was added bromoacetylbromide (0.244 mL, 2.81 mmol). The reaction mixture was allowed toslowly warm to 23° C. A second aliquot of bromoacetyl bromide (0.244 mL,2.81 mmol) was added and the reaction mixture was kept at 23° C. for anadditional 25 min. Water was added (20 mL) and the aqueous layer wasextracted with EtOAc (2×75 mL). The combined organic layers were washedwith brine (25 mL), dried, filtered, and concentrated under reducedpressure. The residue was purified (FCC) (10-45% EtOAc/hexanes) to yieldthe titled compound (0.361 g, 42% yield) after trituration with EtOAc. A3:2 mixture of regioisomers was observed in the ¹H NMR spectrum. MS(ESI/CI): mass calcd. for C₁₉H₂₁BrClN₅O₅, 513.0; m/z found, 514.0[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.89 (s, 1H), 8.87 (br s, 1H), 8.71 (s,1H), 8.18 (s, 1H), 7.70 (s, 1H), 6.13 (s, 2H), 4.36 (q, J=7.2 Hz, 2H),4.13 (s, 2H), 3.68-3.62 (m, 2H), 3.49-3.43 (m, 2H), 3.31 (s, 3H), 1.38(t, J=7.1 Hz, 3H).

Step B:1-[6-Chloro-1-(2-methoxy-ethoxymethyl)-5-(2-morpholin-4-yl-acetylamino)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. To a suspension of1-[5-(2-bromo-acetylamino)-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (0.100 g, 0.194 mmol) and dichloromethane (1 mL) wasadded morpholine (51.0 μL, 0.580 mmol). The reaction mixture was stirredat 23° C. for 50 min. The reaction mixture was partitioned between EtOAc(15 mL) and water (10 mL), and the aqueous layer was further extractedwith EtOAc (2×15 mL). The combined organic layers were washed with brine(15 mL), dried, filtered, and concentrated under reduced pressure, toyield the titled compound (97 mg, 96% yield) as a 3:1 mixture ofregioisomers. MS (ESI/CI): mass calcd. for C₂₃H₂₉ClN₆O₆, 520.2; m/zfound, 521.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 10.00 (s, 1H), 8.89 (s,1H), 8.85 (s, 1H), 8.18 (s, 1H), 7.68 (s, 1H), 6.12 (s, 2H), 4.36 (q,J=7.1 Hz, 2H), 3.87-3.80 (m, 4H), 3.67-3.60 (m, 2H), 3.48-3.42 (m, 2H),3.32 (s, 2H), 3.24 (s, 3H), 2.73-2.67 (m, 4H), 1.38 (t, J=7.1 Hz, 3H).

Step C:1-[6-Chloro-5-(2-morpholin-4-yl-acetylamino)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27, Steps F-G. MS (ESI/CI): mass calcd. for C₁₇H₁₇ClN₆O₄, 404.1; m/zfound, 405.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomeric broadening):13.46 (br s, 1H), 12.95 (br s, 1H), 10.04-9.86 (m, 1H), 8.88 (s, 1H),8.46 (s, 1H), 8.29 (s, 1H), 7.96-7.43 (m, 1H), 3.73-3.65 (m, 4H), 3.21(s, 2H), 2.64-2.56 (m, 4H).

Example 143:1-[6-Chloro-5-(2-piperidin-1-yl-acetylamino)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 142,substituting piperidine for morpholine in Step B, and was recovered asthe hydrochloride salt. MS (ESI/CI): mass calcd. for C₁₈H₁₉ClN₆O₃,402.1; m/z found, 403.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomericbroadening): 13.68 (brs, 1H), 13.00 (brs, 1H), 10.47 (s, 1H), 10.02(brs, 1H), 8.91 (s, 1H), 8.32 (s, 1H), 7.89-7.62 (m, 2H), 4.32-4.13 (m,2H), 3.60-3.45 (m, 2H), 3.21-3.02 (m, 2H), 1.90-1.61 (m, 5H), 1.50-1.33(m, 1H).

Example 144:1-{6-Chloro-5-[2-(4-methyl-piperazin-1-yl)-acetylamino]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 142,substituting N-methylpiperazine for morpholine in Step B. The titledcompound was recovered as the hydrochloride salt. MS (ESI/CI): masscalcd. for C₁₈H₂₀ClN₇O₃, 417.1; m/z found, 418.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆, tautomeric broadening): 13.53 (brs, 1H), 12.98 (brs, 1H),10.67 (brs, 1H), 9.77 (s, 1H), 8.89 (s, 1H), 8.33-8.23 (m, 2H), 7.77 (brs, 1H), 3.50-3.35 (m, 4H), 3.18-3.03 (m, 4H), 2.85-2.70 (m, 5H).

Example 145:1-[6-Chloro-5-(4-methoxy-phenoxy)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 50,substituting 4-methoxy-phenol for 3,4-dichloro-phenol and4,5-dichloro-2-nitro-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₈H₁₃ClN₄O₄, 384.1; m/z found, 385.0 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆): 13.23 (s, 2H), 8.86 (d, J=0.5 Hz, 1H), 8.28 (d,J=0.5 Hz, 1H), 7.75 (s, 1H), 7.13 (s, 1H), 6.95 (s, 4H), 3.75 (s, 3H).

Example 146:1-[6-Chloro-5-(4-chloro-2-fluoro-phenoxy)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 50,substituting 4-chloro-2-fluoro-phenol for 3,4-dichloro-phenol and4,5-dichloro-2-nitro-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₇H₉Cl₂FN₄O₃, 406.0; m/z found, 407.0 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆): 13.33 (s, 1H), 8.87 (s, 1H), 8.29 (s, 1H), 7.79 (s,1H), 7.65 (dd, J=10.9 Hz, 2.5 Hz, 1H), 7.36 (s, 1H), 7.23 (dd, J=8.8 Hz,1.6 Hz, 1H), 6.91 (t, J=8.9 Hz, 1H).

Example 147:1-[6-Chloro-5-(4-trifluoromethoxy-phenoxy)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 50,substituting 4-trifluoromethoxy-phenol for 3,4-dichloro-phenol and4,5-dichloro-2-nitro-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₈H₁₀ClF₃N₄O₄, 438.0; m/z found, 439.0 [M+H]⁺. ¹H NMR(mixture of tautomers, 500 MHz, DMSO-d₆): 13.64 (s, 0.5H), 13.58 (s,0.5H), 12.97 (s, 1H), 8.89 (s, 1H), 8.31 (s, 1H), 7.92 (s, 0.5H), 7.67(s, 0.5H), 7.59 (s, 0.5H), 7.37 (d, J=7.6, 2H), 7.28 (s, 0.5H), 7.03 (s,2H).

Example 148:1-[6-Chloro-5-(3-chloro-4-fluoro-phenoxy)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 50,substituting 3-chloro-4-fluoro-phenol for 3,4-dichloro-phenol and4,5-dichloro-2-nitro-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₇H₉Cl₂FN₄O₃, 406.0; m/z found, 407.0 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆): 8.88 (s, 1H), 8.31 (d, J=0.4 Hz, 1H), 7.79 (s, 1H),7.41 (t, J=9.0 Hz, 2H), 7.19 (d, J=2.8 Hz, 1H), 6.94 (d, J=9.0 Hz, 1H).

Example 149:1-(5-Ethylsulfanyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: 4-chloro-5-ethylsulfanyl-2-nitro-phenylamine. To a solution of5-chloro-2-nitro-4-trifluoromethyl-phenylamine (2.23 g, 9.25 mmol) andDMF (46 mL) was added sodium thioethoxide (2.16 g, 23.1 mmol). Thereaction mixture was heated at 100° C. for 18 h, cooled, and poured intoice/brine (350 mL). The resulting precipitate was collected to yield thetitled compound (2.10 g, 85% yield). This compound did not yield MSdata. ¹H NMR (400 MHz, CDCl₃): 8.41 (s, 1H), 6.59 (s, 1H), 6.38 (s, 3H),3.02 (q, J=7.4 Hz, 2H), 1.43 (t, J=7.4 Hz, 3H).

Step B:1-(5-Ethylsulfanyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27. MS (ESI/CI): mass calcd. for C₁₄H₁₁F₃N₄O₂S, 356.1; m/z found, 357.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.02 (s, 1H), 8.92 (d, J=0.6 Hz,1H), 8.34 (d, J=0.6 Hz, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 3.06 (q, J=7.3Hz, 2H), 1.23 (t, J=7.3 Hz, 3H).

Example150:1-(5-Ethylsulfanyl-6-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 149,substituting 5-chloro-2-nitro-4-trifluoromethoxy-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₄H₁₁F₃N₄O₃S, 372.1; m/z found, 373.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, tautomeric broadening): 13.60 (s, 1H), 12.99 (s, 1H),8.88 (d, J=0.6 Hz, 1H), 8.32 (d, J=0.6 Hz, 1H), 7.83-7.36 (m, 2H), 3.02(q, J=7.3 Hz, 2H), 1.25 (t, J=7.3 Hz, 3H).

Example 151:1-(5-Ethylsulfanyl-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 149,substituting 4,5-difluoro-2-nitro-phenylamine for5-chloro-2-nitro-4-trifluoromethyl-phenylamine in Step A. MS (ESI/CI):mass calcd. for C₁₃H₁₁FN₄O₂S, 306.1; m/z found, 307.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆): 13.46 (s, 1H), 12.97 (s, 1H), 8.87 (d, J=0.6 Hz,1H), 8.30 (d, J=0.6 Hz, 1H), 7.58 (s, 1H), 7.44 (s, 1H), 2.95 (q, J=7.3Hz, 2H), 1.21 (t, J=7.3 Hz, 3H).

Example 152:1-(6-Fluoro-5-propylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A: 4-Fluoro-2-nitro-5-propylsulfanyl-phenylamine. To a mixture of4,5-difluoro-2-nitro-phenylamine (1.51 g, 8.67 mmol), potassiumcarbonate (2.40 g, 17.3 mmol), and DMF (43 mL) was added 1-propanethiol(0.865 mL, 9.54 mmol). The reaction mixture was heated at 90° C. for 1.5h, and allowed to cool to 23° C. The mixture was poured into ice/brine(400 mL) and the resulting precipitate was collected to yield the titledcompound (1.97 g, 98% yield). MS (ESI/CI): mass calcd. for C₉H₁₁FN₂O₂S,230.1; m/z found, 231.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.78 (d, J=10.3Hz, 1H), 6.52 (d, J=6.3 Hz, 1H), 6.04 (s, 2H), 2.93 (t, J=7.3 Hz, 2H),1.84-1.70 (m, 2H), 1.09 (t, J=7.4 Hz, 3H).

Step B:1-(6-Fluoro-5-propylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. The titled compound was prepared in a manner analogous to EXAMPLE27. MS (ESI/CI): mass calcd. for C₁₄H₁₃F₃N₄O₂S, 320.1; m/z found, 321.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomeric broadening): 13.99-12.55(m, 2H), 8.87 (d, J=0.6 Hz, 1H), 8.30 (d, J=0.6 Hz, 1H), 7.87-7.18 (m,2H), 2.91 (t, J=7.1 Hz, 2H), 1.66-1.48 (m, 2H), 0.98 (t, J=7.3 Hz, 3H).

Example 153:1-(6-Fluoro-5-isopropylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 152,substituting 2-propanethiol for 1-propanethiol in Step A. MS (ESI/CI):mass calcd. for C₁₄H₁₃FN₄O₂S, 320.1; m/z found, 321.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆, tautomeric broadening): 13.88-13.19 (m, 1H), 12.97(s, 1H), 8.88 (d, J=0.6 Hz, 1H), 8.30 (d, J=0.6 Hz, 1H), 7.87-7.22 (m,2H), 3.46-3.33 (m, 1H), 1.21 (d, J=6.4 Hz, 6H).

Example 154:1-(5-Ethylsulfonyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 101,substituting 5-chloro-2-nitro-4-trifluoromethyl-phenylamine for4,5-dichloro-2-nitro-phenylamine and sodium thioethoxide for sodiumthioisopropoxide in Step A. MS (ESI/CI): mass calcd. for C₁₄H₁₁F₃N₄O₄S,388.0; m/z found, 389.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomericbroadening): 14.38 (s, 1H), 13.08 (s, 1H), 8.99 (s, 1H), 8.39 (d, J=0.6Hz, 1H), 8.38-7.94 (m, 2H), 3.39 (q, J=7.4 Hz, 2H), 1.18 (t, J=7.4 Hz,3H).

Example 155:1-(5-Ethylsulfonyl-6-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 101,substituting 5-chloro-2-nitro-4-trifluoromethoxy-phenylamine for4,5-dichloro-2-nitro-phenylamine and sodium thioethoxide for sodiumthioisopropoxide in Step A. MS (ESI/CI): mass calcd. for C₁₄H₁₁F₃N₄O₅S,404.0; m/z found, 405.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 14.19 (s,1H), 13.07 (s, 1H), 8.95 (s, 1H), 8.38 (s, 1H), 8.09 (s, 1H), 7.80 (s,1H), 3.40 (q, J=7.4 Hz, 2H), 1.13 (t, J=7.4 Hz, 3H).

Example 156:1-(5-Ethylsulfonyl-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 101,substituting 4,5-difluoro-2-nitro-phenylamine for4,5-dichloro-2-nitro-phenylamine and sodium thioethoxide for sodiumthioisopropoxide in Step A. MS (ESI/CI): mass calcd. for C₁₃H₁₁FN₄O₄S,338.1; m/z found, 339.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomericbroadening): 14.04 (s, 1H), 13.04 (s, 1H), 8.95 (d, J=0.5 Hz, 1H), 8.36(s, 1H), 8.09-7.35 (m, 2H), 3.42 (q, J=7.4 Hz, 2H), 1.15 (t, J=7.3 Hz,3H).

Example 157:1-(6-Fluoro-5-propylsulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 102,substituting 4,5-difluoro-2-nitro-phenylamine for4,5-dichloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₄H₁₃FN₄O₄S, 352.1; m/z found, 353.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆,tautomeric broadening): 14.04 (s, 1H), 13.04 (s, 1H), 8.94 (d, J=0.6 Hz,1H), 8.36 (s, 1H), 8.09-7.46 (m, 2H), 3.44-3.37 (m, 2H), 1.72-1.53 (m,2H), 0.94 (t, J=7.4 Hz, 3H).

Example 158:1-(6-Fluoro-5-isopropylsulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 102,substituting 4,5-difluoro-2-nitro-phenylamine for4,5-dichloro-2-nitro-phenylamine and 2-propanethiol for 1-propanethiolin Step A. MS (ESI/CI): mass calcd. for C₁₄H₁₃FN₄O₄S, 352.1; m/z found,353.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, tautomeric broadening): 14.03(s, 1H), 13.04 (s, 1H), 8.94 (d, J=0.6 Hz, 1H), 8.36 (s, 1H), 8.08-7.45(m, 2H), 3.61-3.46 (m, 1H), 1.22 (d, J=6.8 Hz, 6H).

Example 159:1-(5-Phenylsulfanyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 60,substituting benzenethiol for 3-methyl-benzenethiol and5-chloro-2-nitro-4-trifluoromethyl-phenylamine for4,5-dichloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₈H₁₁F₃N₄O₂S, 404.1; m/z found, 405.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO):8.80 (d, J=0.5 Hz, 1H), 8.11 (s, 1H), 7.92 (s, 1H), 7.63 (s, 1H),7.31-7.26 (m, 2H), 7.20-7.16 (m, 1H), 7.12-7.09 (m, 2H).

Example 160:1-[5-(4-Methoxy-phenylsulfanyl)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 60,substituting 4-methoxy-benzenethiol for 3-methyl-benzenethiol and5-chloro-2-nitro-4-trifluoromethyl-phenylamine for4,5-dichloro-2-nitro-phenylamine in Step A. MS (ESI/CI): mass calcd. forC₁₉H₁₃F₃N₄O₃S, 434.1; m/z found, 435.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO):8.79 (s, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.36 (s, 1H), 7.32 (d, J=8.6Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 3.76 (s, 3H).

Example 161:1-(5-Benzenesulfonyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[1-(2-methoxy-ethoxymethyl)-5-phenylsulfanyl-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 159). MS (ESI/CI): masscalcd. for C₁₈H₁₁F₃N₄O₄S, 436.0; m/z found, 437.0 [M+H]⁺. ¹H NMR (600MHz, DMSO): 14.40 (s, 1H), 13.03 (s, 1H), 8.98 (s, 1H), 8.61 (s, 1H),8.38 (s, 1H), 8.11 (s, 1H), 7.85 (d, J=7.7 Hz, 2H), 7.70-7.66 (m, 1H),7.63-7.58 (m, 2H).

Example 162:1-[5-(4-Methoxy-benzenesulfonyl)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[1-(2-methoxy-ethoxymethyl)-5-(4-methoxy-phenylsulfanyl)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 160). MS (ESI/CI): masscalcd. for C₁₉H₁₃F₃N₄O₅S, 466.1; m/z found, 467.1 [M+H]⁺. ¹H NMR (600MHz, DMSO): 14.35 (s, 1H), 13.05 (s, 1H), 8.97 (s, 1H), 8.55 (s, 1H),8.38 (s, 1H), 8.11 (br s, 1H), 7.81 (d, J=7.9 Hz, 2H), 7.16-7.07 (m,2H), 3.83 (s, 3H).

Example 163:1-[6-Chloro-5-(4-chloro-benzylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 66,Method B, substituting 1-bromomethyl-4-chloro-benzene for benzyl bromidein Step D. MS (ESI/CI): mass calcd. for C₁₈H₁₂Cl₂N₄O₂S, 418.0; m/zfound, 419.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 13.50 (s, 1H), 12.95 (s,1H), 8.87 (s, 1H), 8.29 (s, 1H), 7.84-7.49 (m, 2H), 7.37 (q, J=8.6 Hz,4H), 4.29 (s, 2H).

Example164:1-[6-Chloro-5-(3-chloro-benzylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 66,Method B, substituting 1-bromomethyl-3-chloro-benzene for benzyl bromidein Step D. MS (ESI/CI): mass calcd. for C₁₈H₁₂Cl₂N₄O₂S, 418.0; m/zfound, 419.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.86 (d, J=0.5, 1H),8.28 (d, J=0.5 Hz, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.44 (s, 1H),7.34-7.29 (m, 3H), 4.30 (s, 2H).

Example 165:1-(6-Chloro-5-cyclohexylmethylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 66,Method B, substituting bromomethyl-cyclohexane for benzyl bromide inStep D. MS (ESI/CI): mass calcd. for C₁₈H₁₉ClN₄O₂S, 390.1; m/z found,391.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) 8.87 (d, J=0.5 Hz, 1H), 8.29 (d,J=0.5 Hz, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 2.90 (d, J=6.7 Hz, 2H), 1.88(d, J=12.3 Hz, 2H), 1.69 (dd, J=9.6 Hz, 3.1 Hz, 2H), 1.61 (d, J=10.9 Hz,1H), 1.57-1.47 (m, 1H), 1.25-1.10 (m, 3H), 1.10-1.00 (m, 2H).

Example 166:1-[6-Chloro-5-(2-morpholin-4-yl-ethylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 66,Method B, substituting 4-(2-bromo-ethyl)-morpholine for benzyl bromidein Step D. MS (ESI/CI): mass calcd. for C₁₇H₁₈ClN₅O₃S, 407.1; m/z found,408.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 13.62 (s, 1H), 12.99 (s, 1H),8.86 (s, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.61 (s, 1H), 3.97 (s, 2H),3.71 (s, 2H), 3.50 (s, 2H), 3.41 (s, 2H), 3.35 (s, 2H), 3.12 (s, 2H).

Example 167:1-[6-Chloro-5-(3,4-dichloro-benzylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 66,Method B, substituting 4-bromomethyl-1,2-dichloro-benzene for benzylbromide in Step D. MS (ESI/CI): mass calcd. for C₁₈H₁₁Cl₃N₄O₂S, 452.0;m/z found, 452.9 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 13.52 (s, 1H), 12.95(s, 1H), 8.87 (s, 1H), 8.29 (d, J=0.5 Hz, 1H), 7.86-7.28 (m, 5H), 4.30(s, 2H).

Example 168:1-[6-Chloro-5-(2,6-dichloro-benzylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 66,Method B, substituting 2-bromomethyl-1,3-dichloro-benzene for benzylbromide in Step D. MS (ESI/CI): mass calcd. for C₁₈H₁₁Cl₃N₄O₂S, 452.0;m/z found, 452.9 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.89 (s, 1H), 8.31(s, 1H), 7.72 (s, 1H), 7.57 (s, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.33 (dd,J=8.4 Hz, 7.8 Hz, 1H), 4.38 (s, 2H).

Example169:1-[6-Chloro-5-(4-methyl-benzylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 66,Method B, substituting 1-bromomethyl-4-methyl-benzene for benzyl bromidein Step D. MS (ESI/CI): mass calcd. for C₁₉H₁₅ClN₄O₂S, 398.1; m/z found,399.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.86 (d, J=0.5 Hz, 1H), 8.29(d, J=0.5 Hz, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.27 (d, J=8.0 Hz, 2H),7.12 (d, J=7.8 Hz, 2H), 4.25 (s, 2H), 2.26 (s, 3H).

Example 170:1-[6-Chloro-5-(4-trifluoromethyl-benzylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 66,Method B, substituting 1-bromomethyl-4-trifluoromethyl-benzene forbenzyl bromide in Step D. MS (ESI/CI): mass calcd. for C₁₉H₁₂ClF₃N₄O₂S,452.0; m/z found, 453.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.25 (s,2H), 8.86 (d, J=0.4 Hz, 1H), 8.29 (d, J=0.5 Hz, 1H), 7.70-7.47 (m, 6H),4.40 (s, 2H).

Example 171:1-[5-(2,4-Bis-trifluoromethyl-benzylsulfanyl)-6-chloro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 66,Method B, substituting 1-bromomethyl-2,4-bis-trifluoromethyl-benzene forbenzyl bromide in Step D. MS (ESI/CI): mass calcd. for C₂₀H₁₁ClF₆N₄O₂S,520.0; m/z found, 521.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 13.56 (s,2H), 12.99 (s, 1H), 8.88 (s, 1H), 8.31 (s, 1H), 8.05-7.99 (m, 2H),7.90-7.33 (m, 5H), 4.45 (s, 2H).

Example 172:1-[6-Chloro-5-(2′-cyano-biphenyl-4-ylmethylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 66,Method B, substituting 4′-bromomethyl-biphenyl-2-carbonitrile for benzylbromide in Step D. MS (ESI/CI): mass calcd. for C₂₅H₁₆ClN₅O₂S, 485.1;m/z found, 486.1 [M+H]+. ¹H NMR (400 MHz, DMSO-d₆): 13.50 (s, 1H), 12.98(s, 1H), 8.88 (s, 1H), 8.30 (s, 1H), 7.95 (dd, J=7.7 Hz, 1.0 Hz, 1H),7.78 (td, J=7.7 Hz, 1.3 Hz, 1H), 7.74-7.50 (m, 8H), 4.40 (s, 2H).

Example 173:1-[6-Chloro-5-(4-chloro-phenylmethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[6-chloro-5-(4-chloro-benzylsulfanyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 163). MS (ESI/CI): masscalcd. for C₁₈H₁₂Cl₂N₄O₄S, 450.0; m/z found, 451.0 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 14.01 (s, 1H), 13.02 (s, 1H), 8.96-8.90 (m, 1H), 8.34 (s,1H), 7.87 (s, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.25-7.20 (m, 2H), 4.90 (s,2H).

Example 174:1-[6-Chloro-5-(3-chloro-phenylmethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[6-chloro-5-(3-chloro-benzylsulfanyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 164). MS (ESI/CI): masscalcd. for C₁₈H₁₂Cl₂N₄O₄S, 450.0; m/z found, 451.0 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 14.03 (s, 1H), 13.03 (s, 1H), 8.93 (s, 1H), 8.33 (s, 1H),7.96-7.86 (m, 2H), 7.37 (ddd, J=8.0 Hz, 2.1 Hz, 0.9 Hz, 1H), 7.34-7.28(m, 2H), 7.14 (d, J=7.8 Hz, 1H), 4.91 (s, 2H).

Example 175:1-(6-Chloro-5-cyclohexylmethanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[6-chloro-5-cyclohexylmethylsulfanyl-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 165). MS (ESI/CI): masscalcd. for C₁₈H₁₉ClN₄O₄S, 422.1; m/z found, 423.1 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 14.06 (s, 1H), 13.02 (s, 1H), 8.95 (s, 1H), 8.35 (s, 1H),8.19 (s, 1H), 7.90 (s, 1H), 3.44 (d, J=6.2 Hz, 2H), 1.89-1.81 (m, 1H),1.75 (d, J=10.0 Hz, 2H), 1.60 (dd, J=9.3 Hz, 3.4 Hz, 2H), 1.53 (d,J=11.9 Hz, 1H), 1.22-1.05 (m, 5H).

Example 176:1-[6-Chloro-5-(3,4-dichloro-phenylmethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[6-chloro-5-(3,4-dichloro-benzylsulfanyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 167). MS (ESI/CI): masscalcd. for C₁₈H₁₁Cl₃N₄O₄S, 484.0; m/z found, 484.9 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 14.05 (s, 1H), 13.02 (s, 1H), 8.94-8.93 (m, 1H), 8.35 (s,1H), 8.10-7.82 (m, 2H), 7.57 (d, J=8.3 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H),7.16 (dd, J=8.3 Hz, 2.0 Hz, 1H), 4.93 (s, 2H).

Example 177:1-[6-Chloro-5-(2,6-dichloro-phenylmethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[6-chloro-5-(2,6-dichloro-benzylsulfanyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 168). MS (ESI/CI): masscalcd. for C₁₈H₁₁Cl₃N₄O₄S, 484.0; m/z found, 484.9 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆): 8.95 (d, J=0.5 Hz, 1H), 8.35 (d, J=0.5 Hz, 1H), 8.03-7.85(m, 2H), 7.50 (d, J=7.9 Hz, 2H), 7.41 (dd, J=8.7 Hz, 7.5 Hz, 1H), 5.16(s, 2H).

Example 178:1-(6-Chloro-5-p-tolylmethanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-(4-methyl-benzylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 169). MS (ESI/CI): masscalcd. for C₁₉H₁₅ClN₄O₄S, 430.1; m/z found, 431.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆): 13.98 (s, 1H), 13.02 (s, 1H), 8.93 (s, 1H), 8.34 (s, 1H),8.03 (s, 1H), 7.85 (s, 1H), 7.07 (s, 4H), 4.82 (s, 2H), 2.22 (s, 3H).

Example 179:1-[6-Chloro-5-(4-trifluoromethyl-phenylmethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-(4-trifluoromethyl-benzylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 170). MS (ESI/CI): masscalcd. for C₁₉H₁₂ClF₃N₄O₄S, 484.0; m/z found, 485.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆): 14.05 (d, J=57.4 Hz, 1H), 13.03 (s, 1H), 8.93 (s, 1H),8.35 (s, 1H), 8.10-7.74 (m, 3H), 7.69 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1Hz, 2H), 5.02 (s, 2H).

Example 180:1-[5-(2,4-Bis-trifluoromethyl-phenylmethanesulfonyl)-6-chloro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[5-(2,4-bis-trifluoromethyl-benzylsulfanyl)-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 171). MS (ESI/CI): masscalcd. for C₂₀H₁₁ClF₆N₄O₄S, 552.0; m/z found, 553.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆): 14.10 (s, 1H), 13.04 (s, 1H), 8.96 (s, 1H), 8.36 (s, 1H),8.16 (d, J=8.2 Hz, 1H), 8.13-7.98 (m, 3H), 7.87 (d, J=8.0 Hz, 1H), 5.16(s, 2H).

Example 181:1-[6-Chloro-5-(2′-cyano-biphenyl-4-ylmethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 85,from1-[6-chloro-5-(2′-cyano-biphenyl-4-ylmethylsulfanyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (Intermediate from Example 172). MS (ESI/CI): masscalcd. for C₂₅H₁₆ClN₅O₄S, 517.1; m/z found, 518.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆): 13.97 (s, 1H), 13.03 (s, 1H), 8.93 (s, 1H), 8.34 (s, 1H),7.96 (s, 1H), 7.94-7.83 (m, 2H), 7.76 (td, J=7.9 Hz, 1.3 Hz, 1H),7.60-7.55 (m, 2H), 7.52 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 4.97(s, 2H).

Example 182:1-(1H-Imidazo[4,5-b]quinoxalin-2-yl)-1H-pyrazole-4-carboxylic acid

Step A: 1-Carbamimidoyl-1H-pyrazole-4-carboxylic acid ethyl esterhydrochloride. To a solution of 1H-pyrazole-4-carboxylic acid ethylester (5.00 g, 35.7 mmol), cyanamide (1.50 g, 35.7 mmol), and dioxane(25 mL) was added a solution of 4M HCl in dioxane (9.80 mL, 39.3 mmol).The reaction mixture was heated to 100° C. for 3 h. The reaction wascooled to 23° C. and Et₂O (20 mL) was added. The resulting whiteprecipitate was filtered to yield the titled compound (7.26 g, 93%). ¹HNMR (400 MHz, DMSO-d₆): 9.65 (br m, 4H), 9.29 (s, 1H), 8.43 (s, 1H),4.31 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H).

Step B: 1-(1H-Imidazo[4,5-b]quinoxalin-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester. A solution of 1-carbamimidoyl-1H-pyrazole-4-carboxylicacid ethyl ester hydrochloride (0.220 g, 1.00 mmol),2,3-dichloro-quinoxaline (200 mg, 1.00 mmol), and Cs₂CO₃ (1.63 g, 5.00mmol) in DMF (2 mL) was stirred for 4 h. H₂O (3 mL) was added and themixture was acidified to pH 2 with aqueous 1M HCl to form a whiteprecipitate. The precipitate was filtered, triturated with anhydrousEtOH (2 mL), and filtered to yield the titled compound (0.130 g, 43%).MS (CI): mass calcd. for C₁₅H₁₂N₆O₂, 308.1; m/z found, 309.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): 9.08 (s, 1H), 8.23 (s, 1H), 7.92 (d, J=8.1 Hz,1H), 7.87 (d, J=8.2 Hz, 1H), 7.75 (t, J=7.1 Hz, 1H), 7.59 (t, J=7.5 Hz,1H), 4.31 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).

Step C: 1-(1H-Imidazo[4,5-b]quinoxalin-2-yl)-1H-pyrazole-4-carboxylicacid. A mixture of1-(1H-Imidazo[4,5-b]quinoxalin-2-yl)-1H-pyrazole-4-carboxylic acid ethylester (0.110 g, 0.360 mmol), aqueous KOH (1 M, 3.0 mL) and THF (3.0 mL)was stirred for 4 h. The mixture was concentrated and the aqueousresidue was acidified to pH 2 with 1 M aqueous HCl. The resultingprecipitate was collected by filtration to yield the titled compound(89.0 mg, 89%). MS (ESI/CI): mass calcd. for C₁₃H₈N₆O₂, 280.2; m/zfound, 281.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 13.32-12.37 (br m, 1H),9.03 (s, 1H), 8.19 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.89 (d, J=8.3 Hz,1H), 7.76 (t, J=7.6 Hz, 1H), 7.61 (t, J=7.0 Hz, 1H).

Example 183:1-(6,7-Dichloro-1H-imidazo[4,5-b]quinoxalin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 182,substituting 2,3,6,7-tetrachloro-quinoxaline for2,3-dichloro-quinoxaline in Step B. MS (CI): mass calcd. forC₁₃H₆Cl₂N₆O₂, 349.1; m/z found, 349.0 [M]⁺. ¹H NMR (500 MHz, CD₃OD-d₄):9.23 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 8.03 (s, 1H).

Example 184: 1-(1H-Imidazo[4,5-b]pyrazin-2-yl)-1H-pyrazole-4-carboxylicacid

The titled compound was prepared in a manner analogous to EXAMPLE 182,substituting 2,3-dichloro-pyrazine for 2,3-dichloro-quinoxaline in StepB. MS (ESI): mass calcd. for C₉H₆N₆O₂, 230.2; m/z found, 229.2 [M−H]⁻.¹H NMR (500 MHz, DMSO-d₅): 13.21-12.59 (br m, 1H), 8.93 (s, 1H), 8.41(s, 1H), 8.25 (s, 1H), 8.21 (s, 1H).

Example 185: 1-(6-Chloro-9H-purin-8-yl)-1H-pyrazole-4-carboxylic acid

The titled compound was prepared in a manner analogous to EXAMPLE 182,substituting 4,5,6-trichloro-pyrimidine for 2,3-dichloro-quinoxaline inStep B. MS (ESI/CI): mass calcd. for C₉H₅ClN₆O₂, 264.6; m/z found, 265.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 8.76 (s, 1H), 8.51 (s, 1H), 8.19 (s,1H).

Example 186:1-(6-Chloro-5-phenylsulfamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid

Step A:1-[6-Chloro-5-chlorosulfonyl-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. N-chlorosuccinimide (97.7 mg, 0.732 mmol) was added toa suspension of disulfide (Example 66, Method B, Step C, large scalesynthesis by-product) (0.100 g, 0.122 mmol) in aqueous 2M HCl (0.15 mL,0.305 mmol) and acetonitrile (0.75 mL) at 0° C. The reaction mixture wasstirred for 75 min. At this point it was diluted with EtOAc (20 mL),washed with brine (10 mL), dried, filtered, and concentrated. Theresidue was purified via FCC (5-40% EtOAc/hexanes) to yield the titledcompound (77.0 mg, 66% yield) as a 1:1 mixture of regioisomers. MS(ESI/CI): mass calcd. for C₁₇H₁₈Cl₂N₄O₆S, 476.0; m/z found, 477.0[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.96 (d, J=0.6 Hz, 1H), 8.92 (d, J=0.6Hz, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.23 (d, J=0.5 Hz, 1H), 8.22 (d,J=0.5 Hz, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 6.29 (s, 2H), 6.25 (s, 2H),4.38 (q, J=7.1 Hz, 4H), 3.75-3.67 (m, 4H), 3.51-3.43 (m, 4H), 3.29 (s,3H), 3.29 (s, 3H), 1.43-1.37 (m, 6H).

Step B:1-[6-Chloro-1-(2-methoxy-ethoxymethyl)-5-phenylsulfamoyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester. Aniline (15.8 μL, 0.173 mmol) was added to a solutionof1-[6-chloro-5-chlorosulfonyl-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (75.0 mg, 0.157 mmol) in pyridine (0.79 mL) and thereaction mixture was allowed to stir at 23° C. for 1.5 h. At this pointit was partitioned between EtOAc (20 mL) and water (20 mL). The aqueouslayer was further extracted with EtOAc (20 mL) and the combined organiclayers were washed with brine (10 mL), dried, filtered, andconcentrated. The residue was purified via FCC (5-80% EtOAc/hexanes) toyield the titled compound (36.0 mg, 43% yield). MS (ESI/CI): mass calcd.for C₂₃H₂₄ClN₅O₈S, 533.1; m/z found, 534.1 [M+H]⁺.

Step C:1-(6-Chloro-5-phenylsulfamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester. Hydrochloric acid in dioxane (4M, 0.241 mL) was addedto1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-phenylsulfamoyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (35.0 mg, 65.5 μmol) in ethanol (0.50 mL) and allowedto stir at 23° C. for 2.5 h. The solvent was evaporated and the residuewas purified via FCC (5-100% EtOAc/hexanes) to yield the titled compound(28.7 mg, 98% yield). MS (ESI/CI): mass calcd. for C₁₉H₁₆ClN₅O4S, 445.1;m/z found, 446.0 [M+H]⁺.

Step D:1-(6-Chloro-5-phenylsulfamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid. Lithium hydroxide monohydrate (7.90 mg, 0.188 mmol),1-(6-chloro-5-phenylsulfamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid ethyl ester (28.0 mg, 62.8 μmol), THF (0.24 mL), and water (79 μL)were combined, briefly sonicated, and left to stir at 23° C. for 18 h.Solvent was evaporated and 2 mL water was added. This solution wasbrought to pH 1 with aqueous 1M HCl and the resulting precipitate wascollected and dried to yield the titled compound (20.6 mg, 75% yield).MS (ESI/CI): mass calcd. for C₁₇H₁₂ClN₅O4S, 417.0; m/z found, 418.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-de, tautomeric broadening): 13.96 (s, 1H),13.02 (s, 1H), 10.55 (s, 1H), 8.91 (s, 1H), 8.33 (s, 1H), 8.31-8.08 (m,1H), 7.95-7.53 (m, 1H), 7.26-7.04 (m, 4H), 6.96 (t, J=7.2 Hz, 1H).

Biological Protocols:

As indicated herein (see table above), the biological activity of theexemplified compounds was determined according to the followingprotocols.

Expression and Purification of PHD2₁₈₁₋₄₁₇

The human PHD2 expression construct containing amino acids 181-417 ofGenBank Accession ID NM_022051 was cloned into a pBAD vector(Invitrogen), incorporating both an N-terminal histidine tag and aSmt3-tag, both of which are cleaved by Ulpl. Protein production wasachieved by expression in BL21 cells grown in Terrific Broth containing100 μg/ml ampicillin. Cell cultures were inoculated at 37° C. and grownto an OD₆₀₀ of 0.8. Cultures were induced with 0.1% arabinose and grownovernight at 20° C. with continuous shaking at 225 rpm. Cells were thenharvested by centrifugation and stored at −80° C. Cell pellets weresuspended in Buffer A (50 mM Tris-HCl pH 7.2, 100 mM NaCl, 100 mML-arginine, 1 mM TCEP, 0.05% (w/v) NP-40, 50 mM imidazole) followed bythe addition of lysozyme and benzonase. Cells were lysed by sonicationand the lysate was cleared by centrifugation (15,000 rpm, 90 min, 4°C.). The protein was purified by nickel affinity chromatography using aHisTrap Crude FF column (GE Healthcare). Samples were eluted in Buffer Awith a 50-200 mM imidazole gradient. Cleavage of the Smt tag with Ulplprotease was achieved via overnight incubation with dialyzing againstBuffer A. The PHD2₁₈₁₋₄₁₇ sample was then passed over a second HisTrapCrude FF column (GE Healthcare) to remove uncleaved protein. Theflow-through was then dialyzed into 50 mM MES pH 6.0, 1 mM TCEP, 5 mMNaCl for ion exchange chromatography on a HiTrap SP Cation Exchangecolumn (GE Healthcare). The PHD2₁₈₁₋₄₁₇ protein was eluted with a 0-0.2M NaCl gradient. Fractions were pooled for further purification by sizeexclusion chromatography over a Superdex 75 Size Exclusion Column (GEHealthcare). Final protein was concentrated to 4 mg/ml and dialyzed in10 mM PIPES pH 7.0, 100 mM NaCl, 0.5 mM TCEP. The protein was determinedto have a purity of >95% by gel electrophoresis.

Enzyme Activity Assay

The PHD2₁₈₁₋₄₁₇ polypeptide (3 μg) was pre-incubated for 30 minutes withtest compound prior to assessing the enzymatic activity of thepolypeptide. The PHD enzymatic assay was then performed by transferringthe purified PHD2₁₈₁₋₄₁₇ polypeptide (3 μg) mixture with compound to 0.5ml of reaction mixture containing the following: synthetic HIF-1αpeptide comprising residues [KNPFSTGDTDLDLEMLAPYIPMDDDFQLRSFDQLS] (10μM, California Peptide Research Inc., Napa, Calif.), and[5-¹⁴C]-2-oxoglutaric acid (50 mCi/mmol, Moravek Chemicals, Brea,Calif.) in reaction buffer (40 mM Tris-HCl, pH 7.5, 0.4 mg/ml catalase,0.5 mM DTT, 1 mM ascorbate) for 10 minutes in the presence of compound.The reaction was stopped by addition of 50 μl of 70 mM H₃PO₄ and 50 μlof 500 mM NaH₂PO₄, pH 3.2. Detection of [¹⁴C]-succinic acid was achievedby separating from [5-¹⁴C]-2-oxoglutaric acid by incubating the reactionmixture with 100 μl of 0.16 M DNP prepared in 30% perchloric acid. Next,50 μl of unlabeled 20 mM 2-oxoglutaric acid/20 mM succinic acid, servingas carrier for the radioactivity, was added to the mixture, and wasallowed to proceed for 30 minutes at room temperature. The reaction wasthen incubated with 50 μl of 1 M 2-oxoglutaric acid for 30 additionalminutes at room temperature to precipitate the excess DNP. The reactionwas then centrifuged at 2800×g for 10 minutes at room temperature toseparate [¹⁴C]-succinic acid in the supernatant from the precipitated[¹⁴C]-dinitrophenylhydrazone. Fractions of the supernatant (400 μl) werecounted using a beta counter (Beckman Coulter, Fullerton, Calif.).Inhibition of PHD2₁₈₁₋₄₁₇ activity was measured as a decrease in[¹⁴C]-succinic acid production. The IC₅₀ values were estimated byfitting the data to a three-parameter logistic function using GraphPadPrism, version 4.02 (Graph Pad Software, San Diego, Calif.). IC₅₀ valuesup to 10 μM were quantified otherwise were noted as >10 μM. Allcompounds were diluted at 10 mM in 100% DMSO (w/v) and tested from 10 μMto 3 nM at half-log serial dilutions, with a final concentration of 2%DMSO (w/v) in the assay.

Cellular Assay

Hep-3B cells (ATCC, Manassas, Va.) were plated in 96-well plates at20,000 cells per well in 100 μl of DMEM containing 10% fetal bovineserum, 1% non-essential amino acids, 50 IU/mL of penicillin and 50 μg/mLof streptomycin (all cell culture reagents from Invitrogen, Carlsbad,Calif.). Twenty-four hours after plating, compounds were added andincubated for an additional 24 hours. All test compounds were dissolvedat 10 mM in 100% DMSO (w/v) and were tested under saturating conditionswith final compound concentrations at 100 μM in 1% DMSO (w/v). Fiftymicroliters of the supernatant was then transferred to a human Hypoxiaassay kit (Meso-Scale Discovery, Gaithersburg, Md.). Erythropoietin inthe supernatant was detected according to the manufacturer'sinstructions as follows. EPO detection plates were blocked with 3% BSAin PBS overnight and 50 μl of the supernatant was incubated at roomtemperature in an orbital shaker for 2 h. Twenty-five microliters of 0.5μg/ml anti-EPO detection antibody was added for 2 hours at roomtemperature in an orbital shaker. After 3 washes in PBS, 150 μl of 1×read buffer is added and the plate is then read on the MSD SECTORinstrument. Data was then analyzed by determining the percent of EPOsecretion in the presence of 10 μM or 100 μM compound relative to anassay control compound,7-[(4-Chloro-phenyl)-(5-methyl-isoxazol-3-ylamino)-methyl]-quinolin-8-ol.Data is reported as a percentage of EPO secretion of the controlcompound and shows to be reproducible within 10%.

While the invention has been illustrated by reference to exemplary andpreferred embodiments, it will be understood that the invention isintended not to be limited to the foregoing detailed description.

1. A compound having PHD inhibitor activity of the formula (I):

wherein: n is 2-4 each R¹ is independently selected from H, halo, —C₁₋₄alkyl, —C₃₋₈cycloalkyl, —C₁₋₄perhaloalkyl, trifluoroC₁₋₄alkoxy, —OH, —NO₂, —CN, CO₂H, —OC₁₋₄alkyl, —SC₁₋₄alkyl, —S(C₁₋₄alkyl)-R^(c), —S(O)₂(C₁₋₄alkyl)-R^(c), —S(O)—C₁₋₄alkyl, —SO₂—C₁₋₄alkyl, —S—R^(c), —S(O)—R^(c), —SO₂—R^(c), —SO₂—NH—R^(c), —O—R^(c), —CH₂—O—R^(c), —C(O)NH—R^(c), —NR^(a)R^(b), benzyloxy optionally substituted with R^(d), phenyl or monocyclic heteroaryl optionally substituted with R^(d), —C₃₋₈cycloalkyl optionally containing one or more O, S or N wherein said —C₃₋₈cycloalkyl is optionally substituted with R^(d), and two adjacent R¹ groups may be joined to form an optionally substituted 3-8 member ring optionally containing one or more O, S or N; R^(a) and R^(b) are each independently H, C₁₋₄alkyl, —C(O)C₁₋₄alkyl, —C(O)—R^(c), —C(O)CH₂—R^(e), C₁₋₄alkyl-R^(e), —SO₂—R^(c), —SO₂—C₁₋₄alkyl, phenyl optionally substituted with R^(d), benzyl optionally substituted with R^(d) or monocyclic heteroaryl ring optionally substituted with R^(d); or R^(a) and R^(b) can be taken together with the nitrogen to which they are attached to form an optionally substituted monocyclic heterocycloalkyl ring optionally containing one or more heteroatoms; R^(c) is —C₃₋₈cycloalkyl, phenyl optionally substituted with R^(d), benzyl optionally substituted with R^(d), or a monocyclic heteroaryl ring optionally substituted with R^(d); R^(d) is independently —H, halo, —OH, —C₁₋₄alkyl or —C₁₋₄perhaloalkyl, trifluoroC₁₋₄alkoxy, —OC₁₋₄alkyl, —O-phenyl, or —O-benzyl; R^(e) is —C₃₋₈heterocycloalkyl optionally containing one or more O, S or N; R² and R³ are both H, —CF₃, or C₁₋₃alkyl; each Z is C or N, provided that no more than two Z's can simultaneously be N; and enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof. 2.-11. (canceled) 